KR20190039137A - Combination of ceftibuten and clavulanic acid for use in the treatment of bacterial infections - Google Patents

Abstract

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering clavulanic acid, or a pharmaceutically acceptable salt thereof, for the treatment of a bacterial infection. A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and articles of manufacture, and kits and uses thereof.

Description

Combination of ceftibuten and clavulanic acid for use in the treatment of bacterial infections

The present invention provides for the treatment of bacterial infections using a combination of cephalosporin antibiotic and beta-lactamase inhibitor. Specifically, the present invention provides for the treatment of urinary tract infections, including, but not limited to, multiple urinary tract infections, simple urinary tract infections and acute pyelonephritis, which are caused by a species of Enterobacteriaceae.

Multidrug resistance is very widespread among the enterobacteriaceae, the most prevalent urinary tract pathogens, including the most frequent causative pathogens in multiple urinary tract infections (cUTIs). Many enterobacteriaceae isolates produce extended-spectrum β-lactamases (ESBLs) that are resistant to many available antibiotics, including many oral antibiotics. Currently, the orally administered combination product of cephalosporin and beta-lactamase inhibitor is under clinical development for the treatment of bacterial infections, which are approved in the US or EU or include an infection involving ESBL-producing enterobacteriaceae. Drug resistance to pathogenic bacteria is an increasing problem. New therapies are needed to address these needs. It is an object of the present invention to provide compositions, methods, uses, and articles of manufacture that include those having the desirable characteristics described herein that meet these needs.

Cross-references related to this application

This application is related to U.S. Provisional Application No. 62 / 362,293, filed Jul. 14, 2016, entitled " Combination Product for the Treatment of Bacterial Infections, Method ", U.S. Provisional Application No. 62 / 465,051, filed February 28, 2017, the contents of which are incorporated by reference in their entirety for all purposes.

summary

A combination of cephalosporin antibiotic and beta-lactamase inhibitor is provided herein for use in the treatment of bacterial infections. In some embodiments of the invention, the cephalosporin antibiotic is ceftibuten and the beta-lactamase inhibitor is clavulanate. In some embodiments of the present invention, ceftibuten includes a pharmaceutically acceptable salt or hydrate thereof. In some embodiments of the invention, the clavulanate comprises clavulanic acid or a pharmaceutically acceptable salt thereof. In some embodiments of the invention, the combination provided is effective in treating a bacterial infection caused by Enterobacteriaceae. In some embodiments of the invention, the Enterobacteriaceae species are selected from the group consisting of Citrobacter freundii ), Enterobacter aerogenes , Enterobacter cloacae), E. coli (Escherichia coli), keulrep when Ella pneumoniae (Klebsiella pneumoniae , and isolates of Klebsiella oxytoca . In a further embodiment of the invention, the combined compositions are effective against enterobacteriacephaly which is antibiotic resistant. In some embodiments of the invention, enterobacteriaceae express or produce extended-spectrum beta-lactamase (ESBL).

In some of the embodiments provided herein, the combination of ceftibuten and clavulanate provided herein is for oral administration. In some embodiments of the invention, the combination of ceftibuten and clavulanate provided herein includes, but is not limited to, oral suspension, immediate release capsules or tablets, extended release capsules or tablets or injectable forms , It may be a number of different dosage forms. In some embodiments of the invention, these various forms of drug product may provide equivalent drug exposure.

In any of the embodiments provided herein, a combination composition is provided wherein the formulation is selected from the group consisting of a suspension, a capsule, a tablet, or any other suitable form. In a preferred embodiment of the invention, the formulation is administered orally. In a preferred embodiment of the present invention, the composition is a single formulation.

In some of the embodiments provided herein, the combination of the two agents described in the present invention has several advantages over currently available drugs for the treatment of urinary tract infections, including (1) Greater activity and potency against beta-lactamase-producing enterobacteriaceae, considered resistant to (2) greater activity and efficacy against fluoroquinolone-resistant enterobacteriaceae; (3) the possibility of treating recurrent urinary tract infections or urinary tract infections that do not respond to other drugs; (4) the ability to treat urinary tract infections initially treated with intravenous antibiotics (orally, step-down therapy).

A method of treating a bacterial infection of an individual herein comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to the individual clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is associated with or associated with a bya bacterium expressing an extended-spectrum beta-lactamase (ESBL) And bacterial infections are caused by urinary tract infections (UTIs), upper respiratory infections, lower respiratory infections, primary or catheter related blood infections, neonatal sepsis, intra-abdominal infections, otitis media ), Or a wound infection method. In some embodiments of the invention, the infection comprises at least one infection selected from the group consisting of multiple urinary tract infections, simple urinary tract infections and acute pyelonephritis.

A method of treating a bacterial infection of an individual herein comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; Or CTX-M-15 or CTX-M-14 or CTX-M-15, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, Lt; RTI ID = 0.0 > beta-lactamase (ESBL) < / RTI >

A method of treating a bacterial infection of an individual herein comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to the individual clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is associated with, or caused by, a bacterium expressing an extended-spectrum beta-lactamase (ESBL) Wherein the subject is previously administered an antibiotic to treat a bacterial infection. In certain some embodiments provided herein, the method comprises: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to a subject, wherein the bacterial infection is associated with or is associated with a bacterium expressing an extended-spectrum beta-lactamase (ESBL) And the subject has previously been administered antibiotics to treat bacterial infections.

 A method of treating a bacterial infection of an individual herein comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein component (a) is administered simultaneously, concurrently, or sequentially with component (b) (I) to (iii): (i) component (a) is administered in combination with a total daily dose of 800 to 1800 mg ≪ / RTI > (ii) component (b) is administered to a subject in a total daily dose of 250-750 mg; (iii) the total daily dose of one or both of components (a) and (b) is administered in a divided dose at least twice per day.

As used herein, a method of treating or preventing an Enterobacteriaceae bacterial infection of an individual comprises: (a) orally administering ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, to a subject, wherein the bacterial infection is Associated with or caused by an enterobacteriaceae expressing magnified-spectrum beta-lactamase (ESBL); Wherein the total daily dose of component (a) is administered in an amount of from 800 to 1800 mg and / or at least two divided doses, wherein the divided dose of component (a) is about 300-400 mg; (A) is administered with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is administered orally at a total daily dose of about 250-750 mg and / or twice daily , And the divided dose of component (b) is about 100-250 mg.

A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual herein comprises: (b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to a subject, wherein the bacterial infection is spread-spectrum Associated with or caused by an enterobacteriaceae expressing beta-lactamase (ESBL); The total daily dose of component (b) is administered in an amount of 250-750 mg and / or in a divided dose of two or more times, wherein the divided dose of component (b) is about 100-250 mg; (A) is administered in a total daily dose of about 800-1800 mg, and / or 2 (2) is administered in combination with ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Wherein the divided dose of component (a) is about 300-400 mg.

As used herein, a method of treating an Enterobacteriaceae bacterial infection of an individual comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to a subject, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter- , Neonatal sepsis, intraperitoneal infection, otitis media, or wound infections; And / or the bacterial infection is caused by or associated with an enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL).

As used herein, a method for preventing an Enterobacteriaceae bacterial infection of an individual comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to a subject, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter- , Neonatal sepsis, intraperitoneal infection, otitis media, or wound infections; And / or the bacterial infection is caused by or associated with an enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL).

As used herein, a method of treating or preventing an Enterobacteriaceae bacterial infection of an individual comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to a subject, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter- , Neonatal sepsis, intraperitoneal infections, otitis media, or wound infections and / or bacterial infections are caused by or associated with enterobacteriaceae expressing broad-spectrum beta-lactamase (ESBL); (i) the components (a) and (b) are administered in divided doses two or three times a day, the divided doses of component (a) are from about 300 to 400 mg, The divided dose is about 100-250 mg; And / or (ii) component (a) is administered in a total daily dose of 900 to 1200 mg and component (b) is administered in a total daily dose of 375 to 562.5 mg.

In some of the embodiments provided herein, component (a) is ceftibuten dihydrate. In some of the embodiments provided herein, component (b) is potassium clavulanate.

In some of the embodiments provided herein, one or both of component (a) and component (b) is administered orally. In some of the embodiments provided herein, component (a) is administered simultaneously or sequentially with component (b). In some of the embodiments provided herein, component (a) and component (b) are co-administered with the same pharmaceutical composition.

In some of the embodiments provided herein, component (a) is administered to a subject in a ratio of 1: 1 to 7: 1 to component (b). In some of the embodiments provided herein, component (a) is administered to a subject in a ratio of 1: 1 to 3: 1 to component (b). In some of the embodiments provided herein, component (a) is administered to an individual at a ratio of about 1: 1 to 2: 1 to component (b). In some of the embodiments provided herein, component (a) is administered to a subject in a ratio of 2: 1 to 4: 1 to component (b). In some of the embodiments provided herein, component (a) is administered to a subject in a ratio of 2: 1 to 3: 1 to component (b).

In certain some embodiments provided herein, the method is characterized by one or more of the following (i) to (iii): i) component (a) is administered to a subject in a total daily dose of 800 to 1800 mg Being; (ii) component (b) is administered to a subject in a total daily dose of 250-750 mg; (iii) the total daily dose of one or both of components (a) and (b) is administered in a divided dose at least twice per day. In some of the embodiments provided herein, the method is characterized by (i) wherein the total daily dose is administered in divided doses at least twice per day. In some of the embodiments provided herein, the method is characterized by (ii) wherein the total daily dose is administered in a divided dose at least twice per day. In some of the embodiments provided herein, the method is characterized by (iii) wherein the total daily dose is administered in divided doses at least twice per day.

In some of the embodiments provided herein, component (a) is administered in a total daily dose of 900 to 1200 mg. In some of the embodiments provided herein, component (b) is administered in a total daily dose of 375 to 562.5 mg. In some of the embodiments provided herein, the total daily dose of component (a) is from about 900 to 1200 mg. In some of the embodiments provided herein, the total daily dose of component (b) is from about 375 to 562.5 mg.

In some of the embodiments provided herein, the total daily dose of one or both of components (a) and (b) is administered in a 2-5 divided doses. In some of the embodiments provided herein, the divided doses are administered 2-5 times per day. In some of the embodiments provided herein, the total daily dose of one or both of components (a) and (b) is administered in two or three divided doses. In some of the embodiments provided herein, the divided doses are administered twice or three times a day.

In some of the embodiments provided herein, the divided dose of component (a) is about 300-600 mg. In some of the embodiments provided herein, the divided dose of component (a) is about 300-400 mg. In certain embodiments of the invention, the divided dose of component (a) is about 300-600 mg. In some of the embodiments provided herein, the divided dose of component (a) is about 300-400 mg. In some of the embodiments provided herein, the divided dose of component (a) is about 400 mg. In some of the embodiments provided herein, the divided dose of component (a) is about 300 mg. In some of the embodiments provided herein, the divided dose of component (b) is about 100-250 mg of component (b). In some of the embodiments provided herein, the divided dose of component (b) is about 125-187.5 mg of component (b). In some of the embodiments provided herein, the divided dose of component (b) is about 125 mg of component (b). In some of the embodiments provided herein, the divided dose of component (b) is about 187.5 mg of component (b).

In some of the embodiments provided herein, one or both of components (a) and (b) are formulated into a capsule, a solutab, a sachet, a suspension, or a tablet. In some of the embodiments provided herein, component (a) and component (b) are combined in a single dosage form. In some of the embodiments provided herein, component (a) and component (b) are provided in separate dosage forms. In some of the embodiments provided herein, components (a) and (b) are formulated together. In some of the embodiments provided herein, one or both of components (a) and (b) are formulated into a capsule, and the capsule is 0, 1, or 2 in size. In some of the embodiments provided herein, one or both of components (a) and (b) are formulated for modified or extended release.

In some of the embodiments provided herein, component (a) and component (b) are administered with the food. In certain embodiments herein, component (a) and component (b) are administered without food.

In some of the embodiments provided herein, component (a) and component (b) are self-administered on an outpatient basis and / or by an individual.

In some of the embodiments provided herein, component (a) and component (b) are at least about or about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 Day, 12 day, 13 day, 14 day, 15 day, 16 day, 17 day, 18 day, 19 day, or 20 day. In some of the embodiments provided herein, component (a) and component (b) are administered for about 7 to 10 days.

In certain some embodiments provided herein, the subject is a human.

In some of the embodiments provided herein, the bacteria is enterobacteriaceae. In some of the embodiments provided herein, the bacteria are selected from the group consisting of Citrobacter freundii , Enterobacter aerogenes ), Enterobacter cloacae ), Escherichia coli), keulrep when Ella pneumoniae (Klebsiella pneumoniae , or Klebsiella oxytoca .

In some of the embodiments provided herein, bacterial infections are urinary tract infections (UTI), upper respiratory tract infections, lower respiratory tract infections, primary or catheter related blood infections, neonatal sepsis, intraperitoneal infections, otitis media, or wound infections. In some of the embodiments provided herein, bacterial infections may include recurrent UTIs, complex UTIs, simple UTIs, bacteremic UTIs, acute pyelonephritis, hospital-acquired pneumonia, respiratory- Ventilator-acquired pneumonia, or bronchitis. In certain some embodiments provided herein, bacterial infections are multiple urinary tract infections (cUTIs), acute pyelonephritis, urolithiasis (uUTI), multiple intraperitoneal (cIAI) or community acquired pneumonia (CAP). In some of the embodiments provided herein, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis. In some of the embodiments provided herein, the subject has a kidney dysfunction.

In some of the embodiments provided herein, the ESBL is inhibited by component (b). In some of the embodiments provided herein, the ESBL is CTX-M, TEM, or SHV beta-lactamase. In some of the embodiments provided herein ESBLs are CTX-M-14 or CTX-M-15 or CTX-M groups identical to CTX-M-14 or CTX-M-15. In some of the embodiments provided herein ESBLs are considered to be CTX-M-14 or CTX-M-15, or CTX-M-14 or CTX-M-15. In some of the embodiments provided herein, the bacteria express CTX-M-14. In some of the embodiments provided herein, the bacteria express CTX-M-15.

 In some of the embodiments provided herein, the bacteria further express one or more additional beta-lactamases. In some of the embodiments provided herein, the bacteria further express one or more additional ESBLs. In certain some embodiments provided herein, the at least one additional beta-lactamase is independently CTX-M, FEC, KLUA, KLUG, TEM, TOHO, or SHV beta-lactamase. In some of the embodiments provided herein, the at least one additional beta-lactamase is independently selected from the group consisting of CTX-M, CTX-M-1, CTX-M-2, CTX- CTX-M-9, CTX-M-9, CTX-M-9, CTX-M- M-12, CTX-M-13, CTX-M-14, CTX-M-15, CTX-M-16, CTX- 21, CTX-M-22, CTX-M-23, CTX-M-24, CTX-M-25, CTX-M- 1, KLUA-5, KLUA-6, KLUA-8, KLUA-9, KLUA-10, KLUA-11, KLUG-1, SHV-2, SHV- Or TOHO-1. In some of the embodiments provided herein, one or more additional beta-lactamases, such as one or more additional ESBLs, are independently selected from the group consisting of CTX-M-1, CTX-M-3, CTX- -15, SHV-2, SHV-7, SHV-12, TEM-1, or TEM-OSBL.

In some of the embodiments provided herein, the bacteria have an antibiotic resistance phenotype. In some of the embodiments provided herein, the antibiotic resistance phenotype is resistance to a combination of fluoroquinolone, beta-lactam, or beta-lactam: beta-lactamase inhibitor. In some of the embodiments provided herein, the antibiotic resistant phenotype is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, cefaclor, cefadroxil ), Cefepime, cefixime, ceftibuten, cefdinir, cefditoren, cefotaxime, cefpodoxime, The use of cefprozil, ceftaroline, ceftazidime, ceftriaxone, cefuroxime, cephalexin, cephradine, ciprofloxacin, the compounds of the present invention can be used in combination with ciprofloxacin, doripenem, gentamicin, imipenem, levofloxacin, loracarbef, meropenem, piperacillin, (tobramycin). In some of the embodiments provided herein, the antibiotic resistance phenotype is ST131.

In some of the embodiments provided herein, the bacteria do not express a protein selected from the group consisting of AmpC, KPC, OXA, NDM, or OMP. In some of the embodiments provided herein, the bacteria do not express AmpC. In some of the embodiments provided herein, the bacteria do not express KPC. In some of the embodiments provided herein, the bacteria do not express OXA. In some of the embodiments provided herein, the bacteria do not express NDM. In some of the embodiments provided herein, the bacteria do not express OMP.

In some of the embodiments provided herein, the subject has previously been administered an antibiotic to treat a bacterial infection. In some of the embodiments provided herein, the antibiotic that was previously administered is beta-lactam or fluoroquinolone.

In some of the embodiments provided herein, the antibiotic that has been previously administered is a beta-lactam, which is a penicillin derivative, cephalosporin, monobactam, or carbapenem. In some of the embodiments provided herein, the antibiotics previously administered may be selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, sepracur, sephadoxil, cephipim, sephicem, ceftibuten, Ceftazidime, ceftriaxone, cephroxone, cephalexin, cephradine, doripenem, gentamicin, imipenem, levofloxacin, ceftazidime, , Loracabep, meropenem, piperacillin, or tobramycin beta-lactam. In some of the embodiments provided herein, a previously administered antibiotic is a beta-lactam administered with a beta-lactamase inhibitor. In some of the embodiments provided herein, the previously administered beta-lactamase inhibitor is clavulanate, tazobactam, avibactam, or sulbactam.

In some of the embodiments provided herein, the antibiotic that was previously administered is fluoroquinolone, which is levofloxacin or ciprofloxacin.

In some of the embodiments provided herein, previously administered antibiotics were not effective enough to treat bacterial infections. In some of the embodiments provided herein, a previously administered antibiotic is an intravenously administered antibiotic. In some of the embodiments provided herein, administration of components (a) and (b) is a step-down therapy or an oral part of a therapeutic switch orally in a vein. In any of the embodiments provided herein, components (a) and (b) are administered orally and the oral administration of components (a) and (b) is a stepwise decreasing therapy, or intravenously, Lt; / RTI >

In some of the embodiments provided herein, the IC ₅₀ of component (a) is greater than about 100 μM or 1000 μM for ESBL. In some of the embodiments provided herein, the K _M of component (a) is greater than about 100 μM for ESBL.

In some of the embodiments provided herein, the administration of components (a) and (b) according to the methods provided herein may be carried out with a composition that is greater than 40% fT> MIC, greater than 50% Or systemic exposure of component (a) greater than 60% fT > MIC. In some of the embodiments provided herein, the administration of components (a) and (b) according to the methods provided herein can be carried out with a CT of greater than 20% fT> CT, greater than 25% (B) greater than 40% fT > CT.

In some of the embodiments provided herein, the administration of component (a) and component (b) may be in the range of about 5 ug / mL to 30 ug / mL, 5 ug / mL to 25 ug / mL, ML to about 30 μg / mL, 10 μg / mL to 25 μg / mL, 15 μg / mL to about 30 μg / mL, or 15 μg / mL to about 25 μg / mL, a). < / RTI > In some of the embodiments provided herein, the maximum concentration of component (b) is from about 0.1 [mu] g / mL to 10 [mu] g / mL, 0.1 [ 0.1 to 10 μg / mL, 0.2 to 5 μg / mL, 0.1 μg / mL to 3 μg / mL, 0.1 μg / mL to 3 μg / mL, From about 0.2 μg / mL to about 4 μg / mL, from about 0.2 μg / mL to about 3 μg / mL, from about 0.2 μg / mL to about 1 μg / mL, from about 0.5 μg / mL to about 4 μg / Ug / mL, 1 / / mL to about 3 ㎍ / mL. In some embodiments of the invention, the maximum concentration is the maximum serum concentration.

In some of the embodiments provided herein, the PBLIE of component (b) in combination with component (a) is at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours. In some of the embodiments provided herein, when used in combination with component (b), the MIC of component (a) is less than about 4 ug / mL, less than about 2 ug / mL, less than about 1 ug / Or about 0.5 [mu] g / mL or less. In some of the embodiments provided herein, the MIC of component (a) alone is greater than about 4 [mu] g / mL. In some of the embodiments provided herein, the MIC of component (a) alone may be used in combination with component (b) for the same microorganism, e.g., bacteria, for example ESBL-producing enterobacteriaceae Is about 4 times greater than the MIC of component (a). In some of the embodiments provided herein, the MBC of component (a), when used in combination with component (b), can be used for the same microbe, for example bacteria, for example ESBL-producing enterobacteriaceae Is less than four or two times higher than the MIC of component (a) when component (a) is used in combination with component (b).

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of enterobacteriaceae bacterial infections. Bacterial infections are UTIs, upper respiratory infections, lower respiratory infections, primary or catheter-related blood infections, neonatal sepsis, intraperitoneal infections, otitis media, or wound infections, and optionally bacterial infections (CUTI), acute pyelonephritis, urolithiasis, uATI, multiple intraabdominal infection (cIAI) or community acquired pneumonitis (CAP) and / or bacterial infections are caused by extended-spectrum beta-lactamase RTI ID = 0.0 > ESBL) < / RTI >; The medicament is used to orally administer the divided doses of component (a) and the divided doses of component (b) to a subject, wherein component (a) and component (b) (I) the divided doses of component (a) are for administration of a total daily dose of 800 to 1800 mg; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

As used herein, in the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection, the use of (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, (CUTI), acute pyelonephritis, simple urinary tract infections (UTIs), urinary tract infections, urinary tract infections (UTIs), upper respiratory infections, lower respiratory infections, primary or catheter related blood infections, neonatal sepsis, intraperitoneal infections, otitis media, and / or bacterial infections are associated with or caused by the enterobacteriaceae expressing the extended-spectrum beta-lactamase (ESBL) ; The medicament is used to orally administer the divided doses of component (a) to the individual; Component (a) is administered with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is orally administered in divided doses; The components (a) and (b) are administered in divided doses at least twice per day, and the divided dosages provide for use characterized by one or more of the following: (i) The dosage is for administration of a total daily dose of 800-1800 mg; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

As used herein, in the manufacture of a medicament for treating or preventing an enterobacteriaceae bacterial infection, (b) the use of clavulanic acid, or a pharmaceutically acceptable salt thereof, the bacterial infection is selected from urinary tract infection (UTI), upper respiratory tract infection, (CUTI), acute pyelonephritis, urolithiasis (uUTI), combined abdominal cavity infections (UTIs), multiple urinary tract infections (UTIs), urinary tract infections (CIAI) or community acquired pneumonitis (CAP) and / or a bacterial infection is caused or caused by an enterobacteriaceae expressing an extended-spectrum beta-lactamase (ESBL); The medicament is used to orally administer the divided doses of component (b) to the individual; Component (b) is administered with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is orally administered in divided doses; The components (a) and (b) are administered in divided doses at least twice per day, and the divided dosages provide for use characterized by one or more of the following: (i) The dosage is for administration of a total daily dose of 800-1800 mg; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of enterobacteriaceae bacterial infections. Bacterial infections are UTIs, upper respiratory infections, lower respiratory infections, primary or catheter-related blood infections, neonatal sepsis, intraperitoneal infections, otitis media, or wound infections, and optionally bacterial infections (CUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonitis (CAP) and / or bacterial infections are caused by extended-spectrum beta-lactamase ESBL), and wherein components (a) and (b) are formulated for oral administration The ball. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

In some of the embodiments provided herein, the medicament is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) and component ) Is administered at a dosage of at least two divided doses per day and the divided dose is characterized by one or more of the following: (i) the divided doses of component (a) are from 800 to 1800 mg total daily dose ≪ / RTI > (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the invention, the divided doses of component (a) are administered together with the divided doses of component (b).

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an Enterobacteriaceae bacterial infection, Wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, Infection may be caused by multiple urinary tract infections (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonias (CAP) and / Associated with or caused by an enterobacteriaceae expressing an antigen (ESBL); The pharmaceutical compositions are used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein components (a) and (b) (I) the divided doses of component (a) are for administration of a total daily dose of 800 to 1800 mg, and ; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

A pharmaceutical composition comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for treating or preventing an Enterobacteriaceae bacterial infection, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI) (CUTI), acute pyelonephritis, simple urinary tract infection (uUTI), respiratory tract infections, lower respiratory tract infections, primary or catheter related blood infections, neonatal sepsis, intraperitoneal infections, otitis media, (CIAI) or community acquired pneumonitis (CAP) and / or bacterial infection is caused or caused by an enterobacteriaceae expressing an extended-spectrum beta-lactamase (ESBL); The pharmaceutical composition is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) comprises (b) clavulanic acid, or a pharmaceutically acceptable salt thereof With possible salts, and component (b) is administered orally in divided doses; The components (a) and (b) are administered in divided doses at least twice per day, and the divided doses are characterized by one or more of the following: (i) The dose administered is for administration of a total daily dose of 800-1800 mg; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

(B) a pharmaceutical composition comprising clavulanic acid, or a pharmaceutically acceptable salt thereof, for treating or preventing an Enterobacteriaceae bacterial infection, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, (CUTI), acute pyelonephritis, urolithiasis (uUTI), combined abdominal cavity infections (UTIs), multiple urinary tract infections (UTIs), urinary tract infections (CIAI) or community acquired pneumonitis (CAP) and / or a bacterial infection is caused or caused by an enterobacteriaceae expressing an extended-spectrum beta-lactamase (ESBL); The pharmaceutical composition is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) comprises (b) clavulanic acid, or a pharmaceutically acceptable salt thereof With possible salts, and component (b) is administered orally in divided doses; The components (a) and (b) are administered in divided doses at least twice per day, and the divided doses are characterized by one or more of the following: (i) The dose administered is for administration of a total daily dose of 800-1800 mg; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for treatment or prevention of an enterobacteriaceae bacterial infection, Wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, (CUTI), acute pyelonephritis, urolithiasis, uATI, multiple intraabdominal infection (cIAI) or community acquired pneumonitis (CAP) and / or bacterial infections are caused by extended-spectrum beta-lactamase ESBL), and the pharmaceutical composition is formulated for oral administration. to provide. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

In some of the embodiments provided herein, the composition is used to orally administer a divided dose of component (a) and / or a divided dose of component (b) to a subject, wherein component (a) (b) is administered in a divided dose at least twice per day and the divided dose is characterized by one or more of the following: (i) the divided dose of component (a) is 800-1800 mg total daily For the administration of a dose; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg.

In some of the embodiments provided herein, component (a) and component (b) are combined in a single dosage form. In some of the embodiments provided herein, component (a) and component (b) are provided in separate dosage forms. In some of the embodiments provided herein, component (a) and component (b) are for simultaneous, concurrent, or sequential administration. In some of the embodiments provided herein, component (a) and component (b) are for administration together. In some of the embodiments provided herein, component (a) and component (b) are for administration separately. In some of the embodiments provided herein, component (a) and component (b) are used on an outpatient basis and / or self-administered by an individual.

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the bacterial infection is associated with an enterobacteriaceae expressing an extended-spectrum beta-lactamase (ESBL); And (c) instructions for performing any of the methods described herein.

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the bacterial infection is associated with an enterobacteriaceae expressing an extended-spectrum beta-lactamase (ESBL); And (c) instructions for administering an effective amount of components (a) and (b) to a subject in need thereof for the treatment of a bacterial infection, wherein the bacterial infection is characterized by the expression of an extended-spectrum beta-lactamase (ESBL) Lt; RTI ID = 0.0 > of < / RTI > enterobacteriaceae.

At least two oral dosage forms comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and / or (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, Wherein each dosage form is for oral administration of a unit dose to a subject; At least two oral dosage forms of component (a) and / or at least two oral dosage forms of component (b) are administered to a subject more than once a day, with divided doses of component (a) and / (A) is administered with component (b) and the divided dose is characterized by one or more of the following: (i) the divided dose of component (a) is from 800 to 1800 mg Lt; RTI ID = 0.0 > of: < / RTI > (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

As used herein, a kit for use in the treatment or prevention of an Enterobacteriaceae bacterial infection, comprising: (a) at least two oral dosage forms comprising ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and / or b) at least two oral dosage forms comprising clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter- , Neonatal sepsis, intraperitoneal infection, otitis media, or wound infections. Optionally, the bacterial infection may be a combination of multiple urinary tract infections (cUTI), acute pyelonephritis, urolithiasis, uATI, Pneumonia (CAP) and / or bacterial infection is associated with enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL) From or is caused by; Each dosage form is intended for oral administration of a unit dose to a subject, wherein at least two oral dosage forms of component (a) and / or at least two oral dosage forms of component (b) contain component (a) and / or Wherein component (a) is administered with component (b) and wherein the divided dose is characterized by one or more of the following: (i) The divided doses of component (a) are for administration of a total daily dose of 800-1800 mg; (ii) the divided dose of component (a) is at least about 300 mg; (iii) the divided doses of component (b) are for administration of a total daily dose of 250-750 mg; And / or (iv) the divided dose of component (b) is at least or at least about 100 mg. In some embodiments of the present invention, component (a) is ceftuthene dihydrate. In some embodiments of the present invention, component (b) is potassium clavulanate.

In some of the embodiments provided herein, component (a) and component (b) are combined in a single dosage form. In some of the embodiments provided herein, component (a) and component (b) are provided in separate dosage forms.

In some of the embodiments provided herein, the kit further comprises instructions for use of component (a) and component (b). In some of the embodiments provided herein, the kit further comprises instructions for administering component (a) and component (b) to the subject. In some of the embodiments provided herein, the instructions specify that the kit is for use in the treatment or prevention of Enterobacteriaceae bacterial infections. In some of the embodiments provided herein, the instructions specify that the divided doses of component (a) and component (b) are for administration together. In some of the embodiments provided herein, the instructions specify that the divided doses of component (a) and component (b) are for administration separately. In some of the embodiments provided herein, the instructions specify that the divided doses of component (a) and divided doses of component (b) are for simultaneous, concurrent, or sequential administration. In some of the embodiments provided herein, the instructions specify that component (a) and component (b) are administered on an outpatient basis and / or self-administered by said individual. In some of the embodiments provided herein, the instructions specify that the divided doses of component (a) and the divided doses of component (b) are administered 2-5 times a day. In some of the embodiments provided herein, the instructions specify that the divided doses of component (a) and divided doses of component (b) are administered twice or thrice per day.

In some of the embodiments provided herein, the divided dose of component (a) is 300-600 mg. In some of the embodiments provided herein, the divided dose of component (a) is 300-400 mg. In some of the embodiments provided herein, the divided dose of component (a) is about 400 mg of component (a). In some of the embodiments provided herein, the divided dose of component (a) is about 300 mg of component (a). In some of the embodiments provided herein, the total daily dose of component (a) is from about 900 to 1200 mg. In some of the embodiments provided herein, the divided dose of component (b) is about 100-250 mg. In some of the embodiments provided herein, the divided dose of component (b) is about 125-187.5 mg of component (b). In some of the embodiments provided herein, the total daily dose of component (b) is from about 375 to 562.5 mg. In some of the embodiments provided herein, the divided dose of component (b) is about 125 mg of component (b). In some of the embodiments provided herein, the divided dose of component (b) is about 187.5 mg of component (b).

In some of the embodiments provided herein, the oral dosage form includes a capsule, a solution tower, a suspension, a suspension, or a tablet. In some of the embodiments provided herein, the oral dosage form is a capsule and the capsule is 0, 1, or 2 in size. In some of the embodiments provided herein, one or both of component (a) and component (b) are formulated for modified or extended release.

In some of the embodiments provided herein, component (a) and component (b) are packaged in the same container. In some of the embodiments provided herein, component (a) and component (b) are packaged in different containers. In some of the embodiments provided herein, the container is a divided container and at least two oral dosage forms of component (a) are separated from one another in the divided container and / or at least two oral dosage forms of component (b) And are separated from each other in the divided container. In some of the embodiments provided herein, the container is a blister pack. In some of the embodiments provided herein, the kit contains at least one additional antibiotic. In some of the embodiments provided herein, the additional antibiotic is packaged in a container with component (a) and / or component (b). In some of the embodiments provided herein, additional antibiotics are formulated with component (a). In some of the embodiments provided herein, additional antibiotics are formulated with component (b).

DETAILED DESCRIPTION OF THE INVENTION

(A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering clavulanic acid, or a pharmaceutically acceptable salt thereof, for the treatment of a bacterial infection. A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and articles of manufacture, and kits and uses thereof.

For clarity of disclosure, and not for purposes of limitation, the detailed description is divided into the following subsections. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

I. Definition

Unless defined otherwise, all terms of the technical, scientific and technical terms used herein, and other technical and scientific terms or terms are intended to have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs do. In some instances, terms having generally understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein is not necessarily limited to a substantial It should not be construed as indicating a difference.

All publications, including patent literature, scientific articles and databases mentioned in the present application, are incorporated by reference in their entirety for all purposes to the same extent that each individual publication is individually cited as a reference. Where the definitions provided herein are inconsistent with, or inconsistent with, the definitions set forth in patents, applications, published applications and other publications cited herein as references, the definitions set forth herein are incorporated by reference herein Over the defined definition.

As used herein, the term MIC refers to the minimal inhibitory concentration of an antimicrobial agent that will inhibit the visible growth of microorganisms after a certain period of incubation, e.g., overnight incubation. MIC is important in diagnostic laboratories to identify microbial resistance to antimicrobial agents and to monitor the activity of new antimicrobial agents. MIC is generally considered the most basic laboratory measurement of the activity of an antimicrobial agent for an organism and is reported in units of micrograms / milliliters (μg / mL) or milligrams / liter (mg / L). MIC ₉₀ and MIC ₅₀ are common metrics used to assess the in vitro susceptibility of bacterial isolate cohorts to a particular drug or combination of drugs using the test methods described above. MIC ₉₀ and MIC ₅₀ values represent the lowest concentrations of antibiotics in which 90% and 50% of the isolate is inhibited, respectively. In some embodiments of the invention, MIC ₉₀ is defined as the lowest concentration of antibiotic that inhibits the visible growth of 90% of the microbial isolate after incubation overnight. In some embodiments of the invention, MIC ₅₀ is defined as the lowest concentration of antibiotic that inhibits visible growth of 50% of the microbial isolate after overnight incubation.

The term pharmacokinetics (PK) as used herein refers to the drug concentration over time in plasma (and sometimes other body fluids and tissues) derived from a particular dosage regimen.

The term pharmacodynamics (PD) as used herein refers to the relationship between drug concentration and the resulting pharmacological effect in plasma (and sometimes other body fluids and tissues).

The term PK / PD Index for the antimicrobial agent is a pharmacodynamic parameter expressed as bacteriostasis, 1-log kill or 2-log kill, and is a regression of the MIC of a given bacterial isolate - is related to pharmacokinetic ability to constitute a reaction relationship (PK / PD). The most common PK / PD measures associated with efficacy are the area under the concentration-time curve (AUC) for the MIC ratio, the maximum concentration for the MIC ratio ( _Cmax ), and the percentage of time that the drug concentration exceeds the MIC (T > MIC) (Clin Infect Dis 1998; 26: 1-10). In order to reflect the free or unconjugated (i. E., Considered to be microbiologically active) drugs, these PK / PD indices are related to plasma protein binding Corrected, and expressed as f AUC: MIC, f C _max : MIC, and f T > MIC. The efficacy on the β-lactam class is induced by f T> MIC exposure and the size of 40% f T> MIC is related to the bacteriostatic effect of cephalosporin on enterobacteriaceae (Clin Infect Dis 1998; 26: 1-10).

Cephalosporin is an antibiotic required for the prevention and treatment of infections caused by susceptible bacteria. First-generation cephalosporins are mostly active against Gram-positive bacteria; Subsequent generations have increased activity against Gram-negative bacteria (although they often reduce activity against Gram-positive organisms).

Clavulanate is a beta-lactam drug acting as a mechanism-based beta-lactamase inhibitor. When used in combination with penicillin-group antibiotics, it is not effective in itself as antibiotics, but in bacteria that secrete beta-lactamase, which inactivates many beta-lactam antibiotics, such as penicillin or cephalosporin Antibiotic resistance can be overcome.

The term PBLIE is a post-β-lactamase inhibitor post-β-lactamase inhibitor defined as a continuous inhibition of bacterial growth after the β-lactamase inhibitor component + β-lactamase inhibitor combination of β-lactam has been removed inhibitor effect. This represents the time it takes for the organism to recover from the effects of exposure to the? -Lactamase inhibitor and to resume normal growth in the presence of? -Lactam alone. Therefore, in order to calculate PBLIE, two experimental conditions were compared. First, the bacteria are exposed to beta -lactam alone and the second to the same combination of beta-lactam and beta-lactamase inhibitor. After 1 hour, the cells are washed and resuspended in medium with beta-lactam alone and then monitored for growth over time. The difference in the time it takes two cultures to grow 1-log of colony forming units per mL after washing (J Antimicrob Chemother 2004; 53: 616-619) is the metrics used to define the PBLIE.

As used herein, "treating" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: relief of one or more symptoms due to disease, reduction in the extent of disease, stabilization of disease Preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, A reduction in the dosage of one or more other medicines required to treat a disease (partial or total), an increase in quality of life, and / or an extension of survival. In some embodiments of the invention, the disease is a bacterial infection or result. The methods of the present invention contemplate any one or more of these aspects of treatment.

The term " individual " means a mammal and includes, but is not limited to, a human, a cow, a horse, a feline, a canine, a rodent or a primate . Typically, the entity is a human.

As used herein, the term " effective amount " refers to an amount effective to treat a particular disease, condition or disease, for example to ameliorate, temporarily alleviate, reduce, and / or ameliorate a bacterial infection, ≪ / RTI > the amount of the compound or composition that is sufficient to slow, < RTI ID = In connection with bacterial infections, an effective amount includes an amount sufficient to reduce the total number of bacteria present in the subject and / or slow down the growth rate of the bacteria. In some embodiments of the invention, an effective amount is an amount sufficient to prevent or delay the recurrence of a bacterial infection. In the case of a bacterial infection, an effective amount of the drug or composition is sufficient to (i) reduce the number of bacterial cells; (ii) to some extent inhibit, interfere with, slow down, and preferably stop the proliferation of bacterial cells; (iii) preventing or delaying the occurrence and / or recurrence of a bacterial infection; And / or (iv) alleviate to some extent one or more symptoms associated with bacterial infection.

By " prophylactically effective amount " is meant an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. In some cases, the prophylactically effective amount is less than the therapeutically effective amount, since the prophylactic dose is used prior to or at an early stage of the disease, such as bacterial infection in a subject.

As used herein, the term " simultaneous administration " means that the first and second therapies in combination therapy are administered at any time interval of about 15 minutes or less, such as about 10 minutes, 5 minutes, or 1 minute or less ≪ / RTI > If the first and second regimens are administered simultaneously, the first and second regimens may be administered in the same composition (e.g., a composition comprising both the first and second regimen) or a separate composition (e.g., The first regimen and the second regimen are contained in another composition).

The term " sequential administration ", as used herein, means that the first regimen and the second regimen in the combination regimen are administered over about 15 minutes, such as about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 Min or more. ≪ / RTI > The first regimen or the second regimen may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packages or kits.

As used herein, the term " concurrent administration " means that the first regimen and the second regimen administration in the combination regimen overlap each other.

The term " pharmaceutically acceptable " or " pharmacologically compatible ", as used herein, means a substance that is biologically or otherwise desirable, for example, May be mixed with a pharmaceutical composition administered to a patient without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients are preferably included in the Inactive Ingredient Guide provided by the Food and Drug Administration to meet the requirements of toxicology and manufacturing testing requirements and / or the Food and Drug Administration.

As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

The word " about " in the context of a value or parameter herein is meant to indicate a typical error range for each value that is known to those of ordinary skill in the art to which this invention belongs. In certain embodiments of the invention, reference to about is meant a range 10% higher or lower than the value or parameter, and in other embodiments, 5% or 20% higher or lower than the value or parameter ≪ / RTI > Reference to " about " for a value or parameter herein includes (and will be) described as a value or aspect towards the parameter itself. For example, the description about " about X " includes a description of " X ".

It is understood that aspects and implementations of the invention described herein include " comprising ", " consisting of ", and " consisting essentially of " .

II. Combination therapy

The present disclosure relates to bacterial infections caused by Enterobacteriaceae isolates producing certain types of urinary tract infections (UTIs) and / or extended-spectrum beta-lactamases (ESBLs) A ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof and clavulanic acid, or a salt thereof, for treating a bacterial infection, such as an Enterobacteriaceae bacteria infection, Methods and uses involving the combined administration of a pharmaceutically acceptable salt or hydrate thereof. Also provided are compositions comprising ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And / or clavulanic acid, or a pharmaceutically acceptable salt thereof, for use in, and articles of manufacture, and kits and methods provided. In some embodiments of the invention, the composition is suitable for oral administration.

Certain bacterial infections, including those caused by enterobacteriaceae, are difficult to treat, in part, due to the prevalence of multiple drug resistance. Enterobacteriaceae is one of the most prevalent uropathogens; Enterobacteriaceae Escherichia coli coli) alone accounts for 65% to 85% of UTIs (Foxman et al (2000. ) Ann Epidemiol, 10:..... 509-515; Czaja et al (2007) Clin Infect Dis, 45: 273- 280; Wagenlehner et al. (2015) Clin. Infect. Dis., 63: 754-762). In some aspects of the invention, urinary tract infection (UTI) is the most common bacterial infection acquired in community and hospital settings, resulting in 3 million hospital treatment episodes each year in the United States. The US government includes pyelonephritis and estimates that there are 1,050,000 combined urinary tract infections in the United States annually, with 450,000 community-acquired and 600,000 hospital-acquired infections (Analytical Framework for Examining the Value of Antibacterial Products, US Department of Health and Human Services Task Number HHSP23337004T, 2014). Approximately 79% of these infections are caused by E. coli (Wagenlehner et al. (2015) Lancet, 385: 1949-1956).

Surveillance in Europe (ECDC, EARS-Net, 2016, www.ecdc.europa.eu/sites/portal/), in the United States (Lob et al. (2016), Diagn Microbiol Infect Dis, 85: 459-465) files / documents / antibiotics-EARS-Net-summary-2016.pdf) showed that in many cases E. coli cultured from a urinary source was increasingly resistant to existing antibiotics. For example, isolates from urinary tracts of hospital-associated E. coli with 16% community-acquired performance of 28% have been reported to produce extended-spectrum beta-lactamases (ESBLs) in the US in 2014 (Lob et al. (2016) Diagn Microbiol Infect Dis, 85: 459-465). The prevalence of ESBL-producing E. coli has increased approximately three-fold since 2010 (Lob et al. (2016) Diagn Microbiol Infect Dis, 85: 459-465). 10 to 30% of all clinical enterobacteriaceae isolates in the United States and the European Union produce ESBLs (Paterson et al. (2005) Clin Microbiol. Rev., 18: 657-686; Bush et al. ) Annu. Rev. Microbiol., 65: 455-478). The threat of ESBL-producing enterobacteriaceae is highlighted by the "Serious Threat" of the Centers for Disease Control (CDC) and the "risk / first class" threat of the World Health Organization (WHO).

The majority of ESBL-producing enterobacteriaceae are resistant, in some cases, to beta -lactam antibiotics, except carbapenem. Genes encoding ESBLs are often carried on plasmids carrying resistance genes for other classes of antimicrobial agents (Carattoli et al. (2009) Antimicrob. Agents Chemother., 63: 2227-2238). In some aspects of the invention, the Enterobacteriaceae isolate, including the ESBL-producing E. coli isolate, is a mixture of cephalosporin (hydrolysed by ESBLs) and trimethoprim / sulfamethoxazole resistant to almost all orally available therapies, including drugs such as alfalfa, al. (2014) J Antimicrob Chemother, 69: 1050-1056 and fluoroquinolones, the ESBL- Paterson et al. (2000) Clin Infect Dis, 30: 473-478), which are often transferred to water (MacVane et al. (2014) J. Hosp. Med., 9: 232-238; As determined by using the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, MIC90 is a cephalosporin Which is higher than the breakpoint of susceptibility to ceftazidime and ceftriaxone, trimethoprim / sulfamethoxazole, and fluoroquinolone (levofloxacin) .

Thus, effective treatment of oral antibiotics against enterobacteriacease infections, including cUTIs, is limited by an increased prevalence of resistance mechanisms, such as by ESBLs. In some cases where oral antibiotics are available, they are not entirely effective in treating patients with infection associated with the simultaneous ESBL-producing enterobacteriaceae isolate. For example, in the United States, ESBL-producing E. coli due to urinary tract infection is approximately 85% sensitive to oral nitrofurantoin, an oral antibiotic required for the treatment of urinary tract infections (MacVane et al. (2014) J Hosp Med, 9: 232-238). However, nitrofurantoin is prohibited in patients with pyelonephritis, abscesses around the kidneys, or renal dysfunction (Macrobid® Package Insert, Procter and Gamble Pharmaceuticals, Cincinnati, OH: 2008). However, among patients aged 65 years and older, about 45% of patients with renal dysfunction account for a significant portion of patients with urinary tract infections (Coresh et al. (2007) JAMA, 298: 2038-2047) (ESBL-producing Enterobacteriaceae 80% of patients admitted to the hospital due to urinary tract infection were over 65 years old in one US cohort, and about 35% of patients enrolled in clinical trials of combined urinary tract infection had evidence of kidney dysfunction , And over 50% are reported to have been diagnosed with acute pyelonephritis (Wagenlehner et al. (2015) Lancet, 385: 1949-1956.) Oral fosfomycin is also reported to be associated with urinary tract infection due to ESBL-producing enterobacteriaceae (Vardaka et al. (2016) Int J Antimicrob Agents, 47: 269-285). Phosphomycin has not been approved for use in multiple urinary tract infections, and pyelonephritis or abscess around the kidney In patients with (Monurol® Package Insert. Forest Pharmaceuticals, St Louis, MO: 2007). Therefore, both nitrofurantoin or phosphomycin are suitable for the treatment of urinary tract infections in a substantial proportion of ESBL-producing enterobacteriacephalic patients not.

Other potential oral formulations will not meet the need for oral antibiotics active against ESBL-producing enterobacteriaceae, including inducing UTI. Oral administration of phenemic antibiotics, such as orally administered carbapenem tebipenem, can potentially lead to an increase in carbapenem resistance, particularly in community settings. Oral antibiotics with activity against carbapenemase producers can be used in combination with other intravenous agents (e.g., ceftazidime / avibase) used in the treatment of carbapenem-resistant Enterobacteriaceae (CER) If there is a possibility to choose resistance to avibactam, it may not be suitable for use with ESBL-producers lacking carbapenemase (a vast majority of today's isolates). Delafloxacin and pinafloxacin Fluoroquinolone antibiotics, such as finafloxacin, are not expected to protect such strains because approximately 70% of the ESBL-producing strains are non-susceptible to fluoroquinolones. In addition, certain fluoroquinolones, such as certain fluoroquinolones, Certain antibiotics are associated with negative safety characteristics that make them unsuitable if other treatment options are available. In some aspects of the invention, Recombinant oral antibiotics do not result in adequate systemic exposure after a viable oral dose in order to achieve a PK / PD target in humans. Thus, the use of an antibiotic associated with ESBL-producing enterobacteriaceae, such as a urethral infection, There is no oral therapy effective in the treatment of bacterial infections.

Such as, for example, certain aminoglycosides (amikacin), carbapenems (imipenem, meropenem and doripenem), colistin and tigecycline, Only drugs are certainly active against ESBL-producing enterobacteriaceae (Table 1). Therefore, in the opinion of physicians who wish to provide step-down regimens for the environment and oral pathogens of susceptible pathogens and to shorten the length of hospital stay, it has been shown that a significant proportion of these infections can be adequately treated with oral antibiotics (Mombelli et al. (1999) Arch Intern Med, 159: 53-58), although intravenous therapies such as carbapenem, if available, are available. Unnecessary admission for intravenous therapy is associated with adverse effects on the patient's daily function, costly, and increased likelihood of acquiring hospital infection or cardiogenic damage (Pittet et al. (1994) JAMA (2005) Pharmacoeconomics, 23: 1123-1142; Maki et al. (2006) Mayo Clin Proc. 81: 1159-1171). Consistent with these observations, the acquisition of urinary tract infections by ESBL-producing pathogens is associated with an overall increase in health care costs and deterioration in the results of several health economic outcomes research studies (MacVane et al. (2014) J Hosp Med, 9: 232-238; Maslikowska et al (2016) J Hosp Infect, 92: 33-41; Esteve-Palau et al. (2015) J Infect, 71: 667-674). For example, because of the lack of effective oral options, the number of US patients requiring admission to treat infections due to ESBL-producing enterobacteriaceae increased 2.4-fold from 2000 to 2009 (Zilberberg et al. (2013) Infect. Control Hosp Epidemiol, 34: 940-6).

In some aspects of the present invention, intravenous antibiotics are used in the treatment of UTI due to the possibility of resistance to oral antibiotic therapy. In some aspects of the invention, cUTIs are often treated with carbapenem, which is not an ideal option, for example because the use of increasing carbapenem may be a contributing factor to the transmission of carbapenem-resistant enterobacteriaceae (Swaminathan et al (2013) Infect. Control, Hosp Epidemiol., 34: 809-17). For example, approximately 350,000 patients were treated with carbapenem for UTI in 2014 compared with 60,000 in 2004 (Burlingon, MA: Decision Research Group, Arlington Medical Resources (AMR) Resources Group; 2016).

Therefore, new oral drugs are required for the treatment of these multi-drug resistant infections due to Enterobacteriaceae. In some aspects of the present invention, new oral antibiotics effective to treat bacterial infections caused by or associated with UTI and / or ESBL-producing enterobacteriaceae, including cUTIs, reduce the burden and cost of hospitalization, It reduces penicillin use, reduces complications associated with the use of IV catheters, and minimizes the risk of failure of oral antibiotic therapy. In addition, in an intentional transmission environment of pathogenic bacteria, including the transmission of bacteria engineered to produce ESBLs, the lack of effective oral agents for post-exposure prevention may result in many deaths and overloads of the IV therapy center.

Combination therapies, including the combination administration of ceftibuten, provided herein, for example, a pharmaceutically acceptable salt or hydrate thereof, and a clavulanic acid, for example, a pharmaceutically acceptable salt thereof, The need for an oral agonist effective to treat multi-resistant bacterial infections, such as cUTI or acute pyelonephritis, and / or bacterial infections caused by or associated with ESBL-producing enterobacteriaceae are addressed. In combination therapy, two agents have been found to be particularly effective as oral agents against ESBL-producing enterobacteriaceis, which were not achieved by oral administration, either alone or in combination with other drugs.

As a single agent, oral ceftibuten has now been approved in the United States for the treatment of bacterial infections such as chronic bronchitis, acute bacterial otitis media and acute bacterial exacerbations of sore throat and tonsillitis. Ceftibuten is not required for the treatment of urinary tract infections (complex or simple) or acute pyelonephritis, which is a focus indication of the disclosure provided herein. Clavulanate has now been approved for use with amoxicillin or ticarcillin for a variety of bacterial infections, including urinary tract infections. However, modern ESBL-producing enterobacteriaceae have shown a high level of resistance to the penicillin-clavulanate combination product, for example due to the penicillin resistance tendency.

As described herein, a combination of the currently approved oral-bioavailable third generation cephalosporins alone (e.g., cetearmic, cefpodocin and ceftibuten) and a penicillin / beta-lactamase inhibitor combination Amoxicillin + clavulanate) is not active against enterobacteriaceae producing modern ESBLs, such as CTX-M-15 and / or CTX-M-14. In the United States, the majority of the clinical enterobacteriaceae isolates (70-90%) with the ESBL-phenotype express CTX-M-15 and / or CTX-M-14 ESBLs (Doi et al., (2013) Clin Infect Dis, 56: 641-648). The lack of activity of cephalosporin on ESBL-producing enterobacteriaceae is reflected in the poor outcome of patients infected with these pathogens receiving final therapy with cephalosporin (Paterson et al. (2001) J Clin Microb, 39 : 2206-2212; Lee et al. (2013) Clin Infect Dis, 56: 488-495). Such as ceftolozane / tazobactam (Expert Opin Drug Metab Toxicol 2016; 7: 1-8) and Castanheira et al. (2016) Antimicrob Agents Chemother 60: 4770-71) Commercial combinations of cephalosporin and beta-lactamase inhibitors have been reported to be active against ESBL-producing enterobacteriaceae. However, cephalosporins (ceftolozan or ceftazidime) or beta-lactamase inhibitors (such as tazobactam or avibactam) used in this combination are not orally bioavailable. In summary, the combination of existing oral bioavailable cephalosporin and penicillin / beta -lactamase inhibitors is not active against ESBL-producing enterobacteriaceae, and existing cephalosporin / beta-lactamase inhibitor combinations are active But not orally-bioavailable.

Bioavailable third generation cephalosporin antibiotics (ceftibuten) and beta-lactamase inhibitors (such as caffeine) for the treatment of bacterial infections, such as single, oral formulations (suspensions, capsules, tablets or other forms) ), Which is a compound of the present invention, is disclosed. Reference to clavulanate is understood to mean any form, including free acid or salt forms. In some embodiments of the invention, the beta-lactamase inhibitor is a pharmaceutically acceptable salt of clavulanic acid, such as potassium clavulanate or sodium clavulanate. In some embodiments of the invention, the beta-lactamase inhibitor is selected from the group consisting of:

Or a pharmaceutically acceptable salt or hydrate thereof. It is understood that ceftibuten can be a pharmaceutically acceptable salt or hydrate thereof. In some embodiments of the present invention, the cephalosporin antibiotic is a pharmaceutically acceptable salt of ceftibuten. In some embodiments of the invention, the cephalosporin antibiotic is selected from the group consisting of:

Or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments of the invention, the cephalosporin antibiotic is ceftibetene hydrate.

The combinations provided herein are provided as oral treatment options for enterobacteriaceae caused urinary tract infections, which have activity against ESBL-producing enterobacteriaceae, distinct from conventional prior art therapies. Cephalosporins and clavulanates are, for example, a) lack of recognized activity of cephalosporins, such as cetethbutene on modern pathogens (Pulcini et al. (2012) Clin Infect Dis, 54: 268- 274), and b) clavulanate has a short exposure time due to its rapid elimination (Excerpta Medica, International Congress Series 544; 1980, pages 117-121), higher doses can not withstand the limit (1980) Lancet, 1 (8169): 620-623), which were not previously developed in combination due to observations which assume that the PK / PD target for efficacy can not be met. Prior to the present invention, beta-lactamase inhibitor post-dose effect (PBLIE) data was lacking to support the continued effect of cephalosporin + clavulanate on modern ESBL-producing enterobacteriaceae.

As shown in the following in vitro minimum inhibitory concentration (MIC) and beta-lactamase inhibitor post administration effect (PBLIE) experiments and in the related pharmacokinetic / pharmacodynamic (PK / PD) Addition of boranate to ceftibutene demonstrates activity against bacterial isolates that show resistance to ceftibuten alone. As evidenced by the MIC data, the activity of ceftibuten and clavulanate combinations was particularly effective against isolates containing the most common [beta] -lactamase gene, such as the CTX-M enzyme. In addition, in vitro MIC experiments show that adding clavulanate to ceftibuten has activity against bacterial pathogens that confer resistance to the combination of clavulanate and amoxicillin. In other words, the specific combination of ceftibuten and clavulanate has activity exceeding that predicted from the activity of ceftibuten alone or clavulanate in combination with amoxicillin.

The data herein demonstrate the unique pharmacological and pharmacokinetic properties of ceftibuten and ceftibuten plus clavulanate combinations in relation to their activity against ESBL-producing enterobacteriaceae. Compared to other cephalosporin and clavulanate combinations, the combination of ceftibuten and clavulanate is superior to other combinations, including enhanced activity against ESBL-producing bacteria as compared to other cephalosporin-clavulanate combinations Indicating substantially higher antimicrobial potential. In some aspects of the invention, the finding may contribute to the combination of extended beta-lactamase inhibitor post-dose effects (PBLIE), which may lead to continued inhibition of beta-lactamase after brief exposure to beta-lactamase inhibitors cause. In particular, the combination of ceftibuten and clavulanate demonstrated significantly longer PBLIE than the corresponding post-antibiotic effect (PAE) of cefotubutin alone, suggesting that clavulanate is a potent inhibitor of modern ESBLs Effective protection of ceftibuten from hydrolysis and this effect indicates that the clavulanate concentration extends beyond the time period exceeding the threshold concentration. The results herein show that the combination of ceftutaine and clavulanate causes a longer duration of clavulanate to inhibit the beta -lactamase enzyme as compared to other cephalosporin and clavulanate combinations, , And that the protection of elongated ceftibutene [beta] -lactam leads to bacterial death. In addition, the PBLIE data show for the first time that the combination of ceftibuten + clavulanate is likely to be effective for modern and contemporary ESBL-producing enterobacteriaceae with viable dosing regimens. Exemplary human doses, as evidenced by PK / PD analysis, may be administered to a subject, for example, over a period of, for example, 14 days or more, for example 7-10 days, Includes divided daily doses of butene and clavulanate. In some embodiments of the invention, ceftibuten is administered orally at a total daily dose of 800 to 1800 mg, for example a total daily dose of 900 to 1200 mg, given as 300-400 mg BID or TID And the clavulanate is administered orally at a total daily dose of 250 to 750 mg, for example, 375 to 562.5 mg, given as 100-250 mg or 125 to 187.5 mg BID or TID . If 100-250 mg or 125-187.7 mg BID or TID is given. This finding suggests that certain combinations of ceftibuten plus clavulanate are superior to other combinations of existing oral-bioavailable cephalosporin + beta-lactamase inhibitors, likely to meet PK / PD targets and potentially efficacious Backed.

In some embodiments of the invention, methods and uses of agents and compositions are provided, such as compositions comprising ceftibuten and clavulanate, including pharmaceutical compositions and agents, and treatment of bacterial infections. In some embodiments of the present invention, ceftibuten and clavulanate may be used in combination with amphoteric or clavulanate modified (currently in combination with amoxicillin, ticarcillin or any other antibiotic) in comparison to currently available dosages and dosing regimens of ceftibuten or clavulanate As used herein). For example, ceftibuten alone was approved for clinical use at doses of 400 mg / day (QD). In some embodiments of the invention, the preparations of ceftibuten and clavulanate, such as those formulated together or separately, may be administered for reduced dosing frequency (e.g., once or twice a day) and / But are not limited to, extended release formulations or other specific formulations for a total daily administered amount of ceftibuten and / or clavulanate, increased and / or reduced.

In some embodiments of the invention, the methods and uses of the agents and compositions are for the treatment of bacterial infections. In some embodiments of the invention, the treatment is directed to a urinary tract infection, including, but not limited to, multiple urinary tract infections caused by a species of Enterobacteriaceae family, simple urinary tract infection and acute pyelonephritis. However, in some embodiments of the invention, this combination also has utility in the treatment of bacterial infections by other body parts and / or by other bacterial species. In some embodiments of the invention, the combination provided is a pathogen that produces beta -lactamase enzymes that degrade beta -lactam antibiotics, including pathogens susceptible to other antibiotics and cephalosporins such as ceftibuten .

Thus, the combination of ceftutéen and clavulanate provided is not limited to the currently available third-generation oral cephalosporins (e.g., ceftibuten, cefixime or cefpodocin alone), clavulanate containing oral combinations For example, clavulanate and amoxicillin), as well as a combination of the alternative cephalosporins and clavulanates considered. In some embodiments of the present invention, the ability to administer clavulanate and ceftibuten can be determined in an outpatient setting, including allowing administration of relatively simple dosage forms (e. G., Tablets or capsules) ≪ / RTI > In some aspects of the invention, this concerns the need for hospital environments as well as hospital avoidance in a community setting. In some aspects of the present invention, the provided combination of clavulanate and ceftivuten may provide an option to overcome the problem of resistance to other antibiotics, including overcoming the threat posed by engineering tolerance in bacteria to provide. In some embodiments of the invention, the provided combinations provide, in some aspects of the invention, an alternative to carbapenem use that can limit the spread of carbapenem resistance. In some embodiments of the invention, the orally-available combination therapies of ceftibuten and clavulanate provided may be post-exposure prophylactic and / or therapeutic to protect against civilian population risk, such as those associated with bioterror attacks For example, to provide < RTI ID = 0.0 > a < / RTI >

III. Pharmaceutical compositions and formulations

(A) a pharmaceutically acceptable form thereof (hereinafter referred to as " component (a) "), such as ceftibuten or a pharmaceutically acceptable salt or hydrate thereof, and / or (b) (Hereinafter referred to as " component (b) "), such as clavulanic acid, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments of the invention, component (a) and component (b) may be used in combination with a separate < RTI ID = 0.0 > Is formulated into a pharmaceutical composition. In some embodiments of the invention, component (a) and component (b) may be formulated together for use in accordance with the provided article of manufacture, or for use as a single composition for administration to a subject in accordance with the methods and uses provided, do.

It will be appreciated by those of ordinary skill in the art that there are various chemical and polymorphic forms of the compounds present and that any form is expected for ceftibuten or clavulanic acid in the compositions provided herein. In some embodiments of the present invention, ceftibuten can be in the form of a free form or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof. In some embodiments of the present invention, the hydrate is in the form of a monohydrate, a dihydrate or a trihydrate. In some embodiments of the invention, the clavulanic acid may be in its free form or a pharmaceutically acceptable salt or ester form thereof.

In some embodiments of the invention, component (a) and / or component (b) is a pharmaceutically acceptable salt. In some embodiments of the invention, a pharmaceutically acceptable salt is one or more salts of a given compound having the desired pharmacological activity of the free compound and desired biologically or otherwise. In some embodiments of the invention, the pharmaceutically acceptable salts include salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids. In some aspects of the invention, salts of inorganic bases include, for example, alkali metals such as sodium or potassium; Alkaline earth metals such as calcium and magnesium or aluminum; And ammonia. In some aspects of the invention, salts of organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. In some aspects of the invention, salts of inorganic acids include, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. In some aspects of the invention, the salts of the organic acids may be formed, for example, by reacting with an organic acid such as formic, acetic, trifluoroacetic, fumaric, oxalic, tartaric, maleic, citric, succinic, malonic, methanesulfonic, Sulfonic acid. In some aspects of the invention, salts of basic amino acids include, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

In certain embodiments of the invention, component (a) is ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof. In certain embodiments of the present invention, component (a) comprises a hydrate. In certain embodiments of the present invention, component (a) comprises a pharmaceutically acceptable salt. In certain embodiments of the present invention, component (a) is ceftuthene dihydrate. In certain embodiments of the present invention, component (b) is clavulanic acid or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention, component (b) comprises a pharmaceutically acceptable salt. In certain embodiments of the invention, the salt is sodium or potassium. In certain embodiments of the present invention, component (b) is potassium clavulanate. In certain embodiments of the present invention, component (a) is ceftibuten dihydrate and component (b) is potassium clavulanate.

In some embodiments of the invention, the pharmaceutical composition contains a therapeutically effective amount of component (a) and / or component (b) formulated with one or more pharmaceutically acceptable carriers. In some embodiments of the invention, the pharmaceutically acceptable carrier is a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or any type of formulation aid. Some examples of materials that can act as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository wax; Peanut oil, cottonseed oil; Safflower; Sesame oil; olive oil; Oils such as corn oil and soybean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffering agents such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Water without pyrogen; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffers as well as non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coatings, sweetness, aroma, fragrance, preservatives And the oxidizing agent may also be present, depending on the judgment of the formulator.

In general, component (a) and component (b) are formulated for oral administration and administered orally. The pharmaceutical composition may be formulated for oral administration to an individual, such as a human or other animal. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate, and / or a) starch, lactose, sucrose, , Fillers or extenders such as glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) a wetting agent such as glycerol, d) a disintegrating agent such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, optional silicates and sodium carbonate, e) a dissolution retardant such as paraffin, f) An absorption promoting agent such as an ammonium compound, g) an antioxidant such as, for example, acetyl alcohol and glycerol monostearate, Is mixed with a lubricant such as a humectant, h) an absorbent such as kaolin and bentonite clay, and i) talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, . In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.

In some embodiments of the present invention, similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

In some embodiments of the invention, solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the field of drug formulation. They may optionally contain opacifying agents and may also be a composition which releases only the active ingredient, or preferably, in a particular part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes.

In some embodiments of the present invention, similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols.

In some embodiments of the invention, the active agent (s) may also be in micro-encapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings, release modifying coatings and other coatings well known in the field of drug formulation. In such solid dosage forms, the active compound may be mixed with one or more inert diluents, such as sucrose, lactose or starch. Such dosage forms may also comprise, in the general practice, additional substances other than inert diluents, for example tabletting lubricants and tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. They may optionally contain opacifying agents and may also be a composition which releases only the active ingredient, or preferably, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes.

In some embodiments of the invention, component (a) and component (b) are administered orally as a soft gel capsule containing a liquid. In some embodiments of the invention, component (a) and component (b) are administered in a liquid dosage form, such as an oral suspension, syrup, or elixir. In some aspects of the invention, the liquid dosage forms for oral administration may be in the form of individual dosage units, for example, one teaspoon, one tablespoon, one milliliter, and the like, of component (a) and / or component ) ≪ / RTI > of the composition.

In some embodiments of the invention, the pharmaceutical compositions are formulated in unit dosage forms. In some aspects of the invention, the unit dosage forms are physically discrete units suitable as unitary dosages for human and other mammals, and each unit contains component (a) for administration at a divided dose of the total daily dose, And / or an effective amount of component (b) or a portion thereof. In some embodiments of the invention, the pharmaceutical compositions, including unit dosage forms, are suitable for oral administration. In some embodiments of the invention, exemplary, non-limiting, unit dosage forms include tablets (e.g., chewable tablets), caplets, capsules (e. G., Hard capsules or soft capsules), lozenges , Films, strips, gelatin capsules (gelcap) and syrups. Pharmaceutical formulations and unit dosage forms suitable for oral administration are particularly useful for administration on an outpatient basis and / or for administration where the individual (patient) self-manages the agent.

In some embodiments of the invention, component (a) and component (b) may be administered separately (as individual unit dosage forms) or may be administered as component (a) and component (b) for use in the practice of the methods described herein ). ≪ / RTI > In some aspects of the invention, when administered in separate unit forms, typically the dosage of component (a) and component (b) is administered at about the same time, e.g., simultaneously or within about 3 minutes, 5 minutes, 10 minutes , 15 minutes, or 30 minutes, within about 60 minutes of each other (e.g., self-administered).

In certain embodiments of the present invention, component (a) and component (b) may be present in an amount ranging from about 1: 1 to about 6: 1, 5: 1, 4: , Such as between 1: 1 and 7: 1, such as between 1: 1 or 2: 1. In some embodiments of the invention, component (a) is administered to a subject in a ratio of 1: 1 to 4: 1. In certain embodiments of the present invention, component (a) is administered to a subject in a ratio between 1: 1: 3: 1 to component (b). In some embodiments of the invention, component (a) is administered to a subject in a ratio of about 1: 1 to 2: 1 to ingredient (b). In some embodiments of the invention, component (a) is administered to a subject in a ratio of 2: 1 to 4: 1 to component (b). In some embodiments of the invention, component (a) is administered to a subject in a ratio of 2: 1: 3: 1 to component (b). In some embodiments of the invention, component (a) and component (b) are delivered to the subject in the same unit dosage form (i.e., " co-formulated "). For example, the dosage form may contain a pharmaceutically acceptable carrier, such as component (a) and component (b) and excipients or adjuvants. In some embodiments of the invention, a unit dosage form or pharmaceutical composition containing component (a) and component (b) is formulated for administration (e.g., for oral administration) 1: 1 to 7: 1, such as between about 1: 1 and about 6: 1, 5: 1, 4: 1, 3: 1, or 2: 1. In certain embodiments of the invention, component (a) is formulated to be administered (e.g., orally) to an individual at a ratio between 1: 1: 3: 1 to component (b). In certain embodiments of the present invention, component (a) comprises about 1: 1 and 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: : 1, in a molar ratio between about 1: 1 and about 10: 1.

In certain embodiments of the invention, the pharmaceutical compositions, such as unit dosage forms, contain between about 150-600 mg of component (a), such as between about 150-400, 200-400, or 300-400 mg of the component a). In certain embodiments of the invention, the pharmaceutical compositions, such as unit dosage forms, contain between about 50-250 mg of component (b), for example between about 50-250 mg, 100-200 mg, or 125-187.5 mg And component (b). In some embodiments of the invention, the amounts of component (a) and component (b) are present as separate pharmaceutical compositions. In some embodiments of the invention, the amounts of component (a) and component (b) are formulated together in the same pharmaceutical composition.

In some embodiments of the invention, the two or more unit dosage forms are administered every dose, e.g., every divided dose of the total daily dose. For example, in some embodiments of the invention, a unit dosage form of component (a) (ceftibuten) (e.g., an oral dosage form such as a capsule) is between about 50 and 250 mg, 0.0 > mg, < / RTI > about 100 mg and about 200 mg, respectively. In this embodiment of the invention, the divided doses of component (a) are administered in 1, 2, 3 or 4 unit dosage forms. In some embodiments of the invention, a unit dosage form of component (b) (e.g., clavulanic acid) (eg, an oral dosage form such as a capsule) is between about 50 mg and 250 mg, 62.5 mg to 125 mg, each containing about 62.5 mg and about 125 mg. In some embodiments of the invention, the divided doses of component (b) are administered in 1, 2, 3 or 4 unit dosage forms. In some embodiments of the invention, the amounts of component (a) and component (b) are present as separate pharmaceutical compositions. In some embodiments of the invention, the amounts of component (a) and component (b) are formulated together in the same pharmaceutical composition.

In certain embodiments of the invention, the pharmaceutical compositions may be formulated for oral, mucosal (including sublingual, buccal, rectal, nasal or vaginal) or parenteral (subcutaneous, intramuscular, bolus injections, intraarterial, ). ≪ / RTI > In some embodiments of the invention, the pharmaceutical composition is suitable for oral administration. In some embodiments of the invention, the pharmaceutical composition is formulated as a capsule, a solution top, a suspension, a suspension or a tablet. In some embodiments of the invention, the divided doses are formulated into 1, 2, 3 or 4 capsules, a solution top, a suspension, a suspension or a tablet. In some embodiments of the invention, one or both of components (a) and (b) are formulated into capsules. The capsule can be a standard or non-standard size. In some embodiments of the invention, the capsule is 0, 1 or 2 in size.

In certain embodiments of the invention, the pharmaceutical composition is a suspension. In certain embodiments of the invention, the suspension is fragrant. In certain embodiments of the invention, the suspensions are for use in individuals less than about 18 years old, for example, about 16, 14, 12, 10, 8, 6, 5, 4, 3, 2, .

IV. Usage and Usage

As used herein, a method of treating or preventing a bacterial infection of an individual comprising: (a) administering to a subject a pharmaceutically acceptable form thereof, such as ceftibuten or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof; , And / or (b) a pharmaceutically acceptable form thereof, such as clavulanic acid, or a pharmaceutically acceptable salt or ester thereof. In some embodiments of the invention, a method of treating or preventing a bacterial infection of an individual comprises administering to the subject: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof. In some embodiments of the invention, such methods and uses include methods of treatment and uses involving, for example, administering the composition to a subject having, or suspected or likely to have, a bacterial infection. In some embodiments of the invention, such methods and uses involve the step of administering the composition to a subject, for example, a subject at risk of being exposed to, susceptible to, or at risk of a bacterial infection associated with or causing the bacterial infection , Preventive methods and uses.

In some embodiments of the invention, component (a) and / or (b) is formulated into a pharmaceutical composition. In some embodiments of the invention, the pharmaceutical composition is a pharmaceutical composition as described herein. In some embodiments of the invention, the method comprises administering a pharmaceutical composition comprising component (a) and / or (b). In some embodiments of the methods provided herein, the components (a) and / or (b) may be administered orally, mucosally (including sublingually, buccally, rectally, nasally or vaginally) or parenterally , Bolus injection, intraarterial, or intravenous) administration. In some embodiments of the invention, component (a) is administered orally. In some embodiments of the invention, component (b) is administered orally. In some embodiments of the invention, components (a) and (b) are administered orally. In some embodiments of the invention, one or both of components (a) and (b) are formulated into a capsule, a solution top, a suspension, a suspension or a tablet. In some embodiments of the invention, component (a) and component (b) are administered in a total daily dose comprising one or more divided dosages, wherein the divided doses are 1, 2, 3 or 4 capsules, Tops, shakes, suspensions or tablets. In some embodiments of the invention, one or both of components (a) and (b) are formulated into capsules. The capsule can be a standard or non-standard size. In some embodiments of the invention, the capsule is 0, 1 or 2 in size. In some embodiments of the invention, one or both of components (a) and (b) are formulated for modified or extended release.

In some embodiments of the invention, components (a) and (b) are administered in an amount effective to effect a therapeutic or prophylactic treatment of a bacterial infection. Uses include the use of components (a) and (b), or compositions or compositions containing such components, in such methods and treatments, and in the manufacture of a medicament for performing such therapeutic and prophylactic methods. In some embodiments of the invention, the method of treatment comprises treating a bacterial infection in an individual or preventing or reducing the risk of bacterial infection in the subject.

Of the methods and uses for use provided herein, there is a method of treating a bacterial infection, such as an Enterobacteriaceae bacterial infection, in an individual in need of treatment comprising administering to the subject: (a) ceftibuten or its pharmaceutical Acceptable salts, or hydrates thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof. In some embodiments of the invention, the method is for treating an individual who exhibits one or more signs or symptoms of a bacterial infection or an individual known to have a suspected or bacterial infection. In some embodiments of the invention, the method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of multiple urinary tract infections (cUTIs), acute pyelonephritis, simple UTIs, uveitis, acute pyelonephritis, upper respiratory infections, lower respiratory infections, primary or catheter- Such as neonatal sepsis, intra-abdominal infection, otitis media, or wound infection. In some embodiments of the invention, the method comprises administering to a patient a therapeutically effective amount of a compound selected from the group consisting of multiple urinary tract infections (cUTIs), acute pyelonephritis, simple UTIs, multiple intraperitoneal infections (cIAIs), or community acquired pneumonia Or to treat a suspected individual. In some embodiments of the invention, an individual is suspected of having or suspected of having, or suspected of having, a bacterial infection caused by, or associated with, a bacterium expressing extended-spectrum beta-lactamase (ESBL) high. In some embodiments of the invention, the bacterial infection is present on an average of at least about 10% of such individuals, for example, one or more of those individuals with an infection, for example, one of those likely to be associated with ESBL expressing bacteria, At least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% Or is known to be related. In some embodiments of the invention, the subject is selected or identified as having a bacterial infection by ESBL-producing bacteria.

In one aspect of the invention there is provided a method of use or use of a component (a) and / or (b) for treating a bacterial infection in an individual, the method comprising: (a) providing ceftibuten or its pharmaceutically acceptable Possible salts, or hydrates thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter- , Secondary blood infections with UTI causes, neonatal sepsis, intraperitoneal infections, otitis media, or wound infections. In some embodiments of the invention, the bacterial infection is multiple urinary tract infections, simple urinary tract infections, and acute pyelonephritis. In some embodiments of the invention, the bacterial infection is associated with, caused by, associated with, or caused by a bacterium expressing magnified-spectrum beta-lactamase (ESBL). In certain embodiments of the invention, the bacterial infection is a hospital-associated infection or a community acquired infection.

In certain embodiments of the invention, the bacterial infection is associated with two or more bacterial strains. In certain embodiments of the invention, one or more of the two or more strains of bacteria are the bacteria described herein. In certain embodiments of the invention, one or more of the two or more bacterial strains express the expanded-spectrum beta-lactamase (ESBL).

In some embodiments of the invention, the method is for the prevention of an individual susceptible to bacterial infection or susceptible to exposure to bacterial infection. Among the methods and uses of use provided herein are preventative methods, such as preventing, reducing or ameliorating the risk of bacterial infection of an individual, which method comprises (a) ceftibuten or a pharmaceutically acceptable salt thereof, or Their hydrates; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention, one or both of components (a) and (b) are administered after the individual is likely to have been or has been exposed to the bacteria associated with the bacterial infection. In certain embodiments of the invention, the bacteria express magnified-spectrum beta-lactamase (ESBL).

In another aspect of the present invention there is provided a method of use or use of component (a) and / or (b) for treating a bacterial infection in an individual, or for preventing, reducing or ameliorating the risk of bacterial infection in an individual, The method comprises (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to the individual a clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is associated with, or associated with, a bacterium expressing extended-spectrum beta-lactamase (ESBL) . In some embodiments of the invention, the bacterial infection is associated with, or associated with, a bacterium that expresses magnified-spectrum beta-lactamase (ESBL) that is or is thought to be CTX-M-14 or CTX-M- There is a high possibility.

In another aspect of the present invention there is provided a method of use or use of component (a) and / or (b) for treating a bacterial infection in an individual, or for preventing, reducing or ameliorating the risk of bacterial infection in an individual, The method comprises (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to the individual clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein the bacterial infection is associated with a bacterium expressing an extended-spectrum beta-lactamase (ESBL) Previously, antibiotics were administered to treat bacterial infections.

In some embodiments of the invention, the subject is a mammal. In some embodiments of the invention, the subject is a human, a primate, a cow, a goat, a sheep, a pig, a horse, a cat, a dog, or a rodent. In some embodiments of the invention, the subject is a human. In some embodiments of the invention, the subject is a domestic animal. In some embodiments of the invention, the subject is an agricultural animal.

In some embodiments of any method or use provided herein, a subject diagnosed with or suspected of having a bacterial infection can be treated. In some embodiments of the invention, the subject exhibits one or more symptoms of infection. In some embodiments of the invention, the symptoms of the infection are pain, fever, drainage, redness, swelling, drowsiness, headache, cough, chest pain, or dyspnea. In some embodiments of the invention, the subject has been tested positive for bacterial infection. Whether an individual is positive for bacterial infection can be determined by one of ordinary skill in the art. The presence of a bacterial infection can be determined, for example, by culture, PCR, ELISA, sequencing or microarray analysis.

In some embodiments of the invention, the subject is a human. In some embodiments of the invention, the subject is at least about 21, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, In some embodiments of the invention, the subject is a child. In some embodiments of the invention, the subject is any of about 21, 18, 15, 12, 10, 8, 6, 5, 4, 3, 2, In some embodiments of the invention, the subject is male. In some embodiments of the invention, the subject is female. In some embodiments of the invention, the subject has any type of bacterial infection described herein.

In some embodiments of the invention, the subject has previously been administered an antibiotic to treat a bacterial infection. In some embodiments of the invention, the previously administered antibiotic was beta-lactam or fluoroquinolone.

In some embodiments of the invention, the antibiotic previously administered is a beta-lactam, a penicillin derivative, cephalosporin, monobactam, or carbapenem. In some embodiments of the invention, the antibiotic that has been previously administered is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, sephacler, sephadoxil, cephipim, sephicem, ceftibuten, , Ceftazidime, cephofoxin, cephprozil, ceftaroline, ceftazidime, ceftriaxone, seproxime, cepharaxine, sepradine, doripenem, gentamycin, imipenem, levofloxacin, loracabef, Nem, piperacillin, or tobramycin beta-lactam.

In some embodiments of the invention, the previously administered antibiotic is a beta-lactam administered with a beta-lactamase inhibitor. In some embodiments of the invention, the previously administered beta-lactamase inhibitor is clavulanate, tazobactam, avibactam, or sulbactam.

In some embodiments of the invention, the previously administered antibiotic is levofloxacin, dellafloxacin, pinafloxacin, or fluoroquinolone, which is ciprofloxacin.

In some embodiments of the present invention, previously administered antibiotics were not effective enough to treat bacterial infections. In some embodiments of the invention, the bacterial infection is a recurrent bacterial infection. In some embodiments of the invention, previously administered antibiotics were not effective in treating bacterial infections.

In some embodiments of the invention, the previously administered antibiotic is an intravenously administered antibiotic or an oral antibiotic. In some embodiments of the invention, the previously administered antibiotic is an intravenously administered antibiotic.

In some embodiments of the invention, components (a) and (b) are administered orally and the oral administration of components (a) and (b) is a stepwise decreasing therapy or an oral part of a sequential orally intravenous route .

In certain embodiments of the invention, one or both of components (a) and (b) are administered on an outpatient basis. In certain embodiments of the invention, one or both of components (a) and (b) are self-administered by an individual.

In certain embodiments of the invention, component (a) is ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof. In certain embodiments of the present invention, component (a) comprises a hydrate. In certain embodiments of the present invention, component (a) comprises a pharmaceutically acceptable salt. In certain embodiments of the present invention, component (a) is ceftuthene dihydrate.

In certain embodiments of the present invention, component (b) is clavulanic acid, or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention, component (b) comprises a pharmaceutically acceptable salt. In certain embodiments of the invention, the salt is sodium or potassium. In certain embodiments of the present invention, component (b) is potassium clavulanate. In certain embodiments of the present invention, component (a) is ceftibuten dihydrate and component (b) is potassium clavulanate.

In certain embodiments of the present invention, component (a) comprises between about 1: 1 and 7: 1, such as between about 1: 1 and about 6: 1, 5: 1, 4: 1 , 3: 1, or 2: 1. In certain embodiments of the invention, component (a) is administered to an individual in a ratio of 1: 1-3: 1 to component (b). In some embodiments of the invention, component (a) is administered to an individual at a ratio of about 1: 1 to 2: 1 to component (b). In some embodiments of the invention, component (a) is administered to a subject in a ratio of 2: 1 to 4: 1 to ingredient (b). In some embodiments of the invention, component (a) is administered to an individual at a ratio of 3: 1 to 4: 1 to component (b).

In some embodiments of the invention, components (a) and (b) are administered sequentially, concurrently, or concurrently. In certain embodiments of the invention, components (a) and (b) are administered at time intervals of about 15 minutes or less, such as about 10 minutes, 5 minutes, or 1 minute or less. In certain embodiments of the invention, components (a) and (b) are administered at intervals of greater than about 15 minutes, such as any of about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes . Component (a) or component (b) may be administered first. In certain embodiments of the invention, components (a) and (b) are administered simultaneously. In certain embodiments of the invention, components (a) and (b) are co-administered with the same pharmaceutical composition.

The subject may be given a combined administration of component (a) and component (b) at a predetermined time, at an unspecified time, or until an endpoint is reached. In some embodiments of the invention, the treatment may be continued on a continuous daily basis for days, weeks, or months. In some embodiments of the invention, the administration is effective until bacterial reduction and / or until a bacterial infection is no longer detected or present. In accordance with the methods provided herein, components (a) and (b) can be administered in a period of time, such as a continuous day, until the bacterial infection is treated and / or until one or more of the signs or symptoms of bacterial infection are reduced or relieved ≪ / RTI > In some embodiments of the invention, components (a) and (b), for example in connection with a prophylactic method, are administered for a period of time, such as a continuous day, until the risk of bacterial infection is reduced, do.

In certain embodiments of the invention, one or both of component (a) and component (b) may be present for at least about 3 days, such as at least about 4, 5, 6, 7, 8, 9, 12, 13, 14, 15, or 20 days. In certain embodiments of the present invention, one or both of component (a) and component (b) may be administered for from about 3 days to about 20 days, such as from about 3 days to about 20, 15, 14, 13, 12, 10, 9, 8, 7, 6, 5 or 4 days, or about 5 days to about 20, 15, 14, 13, 12, 11, 10, 9, or 8 days. In certain embodiments of the invention, one or both of component (a) and component (b) is administered for about 7 days to about 10 days. In certain embodiments of the present invention, one or both of component (a) and component (b) may comprise from about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, or 20 days. In certain embodiments of the invention, one or both of component (a) and component (b) is administered for 7 to 10 days. In any of these embodiments of the invention, component (a) and component (b) are administered daily for consecutive days.

In some embodiments of the invention, the treatment may be interrupted or paused after a predetermined number of days or specific endpoints, such as a reduction in signs or symptoms of bacterial infection and / or absence of detectable infection in an individual. In some embodiments of the invention, treatment is stopped and paused until the bacterial infection returns to a detectable level and / or until the subject exhibits one or more signs or symptoms of a bacterial infection.

In some embodiments of the invention, the method comprises administering to a subject a therapeutically effective amount of component (a) and / or component (b) for the treatment or prophylactic treatment of a bacterial infection. In some aspects of the invention, the total daily dose administered for the treatment or prophylactic treatment of a particular bacterial infection will vary depending upon the host treated, the route of administration, and the severity of the disease being treated. Thus, the optimal dose may be determined by the physician treating any particular patient. For example, it may be necessary or desirable to reduce the above-mentioned dose to reduce toxicity.

In some embodiments of the present invention, the provided method comprises administering about 500 mg to 2000 mg of component (a), such as about 900, 800, 700 mg, or about 800 to about 1800, 1600, 1500, 1400, 1300, 1200 , 1100, 1000 or 900 mg or about 900 to about 1800, 1600, 1500, 1400, 1300, 1200, 1100 or 1000 mg, or about 1200 to about 1800, 1600, 1500, 1400 or 1300 mg To a subject, e. G., A human. In some embodiments of the invention, the total daily dose is about 600 to 1800 mg, 600 to 1600 mg, 600 to 1400 mg, 600 to 1200 mg, 600 to 1000 mg, 600 to 900 mg, 800 to 800 mg, 800 to 1500 mg, 800 to 1600 mg, 800 to 1400 mg, 800 to 1200 mg, 800 to 1000 mg, 800 to 900 mg, 900 to 2000 mg, 900 to 1800 mg, 900 1000 mg to 1000 mg, 1000 mg to 1200 mg, 1200 mg to 2000 mg, 1000 mg to 1000 mg, 1000 mg to 1500 mg, 1000 mg to 1200 mg, 1200 mg to 1800 mg, 1200 mg to 1600 mg, 1200 mg to 1400 mg, 1400 mg to 2000 mg, 1400 mg to 1800 mg, 1400 mg to 1600 mg, 1600 mg to 2000 mg, mg to 2000 mg. In some embodiments of the invention, the provided method comprises administering about 250 mg to 750 mg, for example about 375 mg, or about 375 to about 750, 600, 562.5, 500, or 400 mg, or about 500 mg to about 750 mg, Such as about 750, 600, or 562.5 mg, or about 562.5 to about 750 or 600 mg, per day. In some embodiments of the invention, the total daily dose is about 250 to 600 mg, 250 to 600 mg, 250 to 500 mg, 250 to 375 mg, 250 to 300 mg, 300 to 750 mg, 600 mg, 300 to 750 mg, 300 to 600 mg, 300 to 500 mg, 300 to 375 mg, 375 to 750 mg, 375 to 600 mg, 375 to 500 mg, 500 to 750 mg, 500 to 600 mg, 750 mg. In some embodiments of the invention, the total daily dose of component (b) is from about 375 to 562.5 mg, including, for example, about 375 mg or about 562.5 mg. In some embodiments of the invention, the provided method comprises administering each component (a) in a total daily dose of 800-1800 mg, and administering component (b) in a total daily dosage of 250-750 mg . In some embodiments of the invention, the provided method comprises administering each component (a) in a total daily dosage of 900 to 1200 mg, and administering component (b) in a total daily dose of 375 to 562.5 mg . In some embodiments of the invention, components (a) and (b) are administered together at the same time. In some embodiments of the invention, components (a) and (b) are formulated for administration together. In some embodiments of the present invention, components (a) and (b) are formulated into separate compositions, e.g., for administration together or concurrently.

In some embodiments of the invention, the total daily dose of one or both of component (a) and component (b) is administered in a single dose or in divided doses two or more times. In some aspects of the invention, the divided doses may be administered to a subject, e. G., A human, in any one day period (e. G., A 24 hour period from midnight to midnight) It is divided into two or more parts, and these parts are administered. In some embodiments of the invention, the total daily dose is administered in a 2-5 divided doses, wherein the divided doses are administered 2-5 times per day. In some embodiments of the invention, the total daily dose is administered in 2-3 divided doses, the divided doses being administered twice or thrice daily. In some embodiments of the invention, component (a) and component (b) are administered as BID (twice daily). In some embodiments of the invention, component (a) and component (b) are administered TID (three times a day). In some embodiments of the invention, the divided dose per day of component (a) is administered in an amount of 300-400 mg, for example about 300 mg or 400 mg. In some embodiments of the invention, the divided doses per day of component (b) may be in the range of 100-250 mg, 125-187.5 mg, such as 125 mg or 187.5 mg, or about 125 mg or 187.5 mg .

In some embodiments of the present invention, the method comprises administering to a subject, e. G., A human, in a two or three divided doses containing 300-400 mg, for example 400 mg or about 400 mg, And administering to the subject in two or three divided doses each containing 100-250 mg, 125-187.5 mg, such as 125 mg or 187.5 mg, or about 125 mg or 187.5 mg, respectively, of clavulanic acid , E. G., A human subject.

In some embodiments of the present invention, the time interval between divided doses of component (a) and / or component (b) is between the respective divided doses containing the components between, or between about 0 and 12 hours For example about 0 and 8 hours, 0 and 6 hours, 0 and 4 hours, 0 and 2 hours, 0 and 1 hour, 1 hour and 12 hours, 1 hour and 8 hours, 1 hour and 6 hours, 1 Hours and 4 hours, 1 and 2 hours, 2 hours and 12 hours, 2 hours and 8 hours, 2 hours and 6 hours, 2 hours and 4 hours, 4 hours and 12 hours, 4 hours and 8 hours, 4 hours and 6 hours, 6 hours and 12 hours, 6 hours and 8 hours, or between 8 hours and 12 hours. In certain embodiments of the present invention, the divided doses of component (a) and / or component (b) may be greater than about 1 hour, for example, any of 2, 3, 4, 5, 6, 7, , 10, 11, or 12 hours over a period of time between each divided dose containing the components. In certain embodiments of the invention, the divided doses may be administered in an amount greater than about 1 hour, such as any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, Administered at intervals of time between divided doses. In certain embodiments of the invention, the divided doses are administered every about 3 to about 12 hours, such as every about 3 hours to about 10, 9, 8, 7, 6, 5, or 4 hours, or about 4 hours About every 12 hours, about every 6 hours, about every 12, 10, 9, 8, or 7 hours, or about every 8 hours, about 12, 10, Administered every 9 hours. In certain embodiments of the invention, the divided doses are administered about every 3, 4, 6, 8 or 12 hours. In certain embodiments of the invention, the divided doses are administered every about 8 or 12 hours.

In some embodiments of the invention, each divided dose containing component (a) and / or component (b) comprises the same amount of one or both of component (a) and component (b). In some embodiments of the present invention, at least one divided dose containing component (a) and / or component (b) has a different amount of component (a) compared to the second divided dose given at the same day, And component (b). In some embodiments of the present invention, the first divided dose administered per day comprises less than one component (a) and one of components (b) less than one or more divided dose (s) administered sequentially on the same day Or both. In some embodiments of the invention, the first divided dose administered per day comprises the minimum amount of one or both of component (a) and component (b) administered per day.

In some embodiments of the present invention, the first divided dose administered per day is one or more doses of one or both of component (a) and component (b) in an amount greater than one or more divided doses (s) . In some embodiments of the invention, the first divided dose administered per day comprises the maximum amount of one or both of component (a) and component (b) administered per day. In some embodiments of the invention, the first divided dose administered per day comprises 300 mg of component (a), and the at least one sequential divided dose (s) comprises greater than 300 mg. In some embodiments of the invention, the first divided dose administered per day comprises 400 mg of component (a), and the at least one sequential divided dose (s) comprises less than 400 mg. In some embodiments of the invention, the first divided dose administered per day comprises 125 mg of component (b), and the at least one sequential divided dose (s) comprises greater than 125 mg. In some embodiments of the invention, the first divided dose administered per day comprises 187.5 mg of component (b) and the one or more sequential divided dose (s) comprise less than 187.5 mg.

In certain embodiments of the invention, one or both of component (a) and component (b) is administered with or without food. In certain embodiments of the invention, one or both of component (a) and component (b) are administered before, together, or after the food. In certain embodiments of the invention, the food is administered for about 2 hours, such as about 1.5 hours, 1.25 hours, 1 hour, 55 minutes, 50 minutes, , 45 minutes, 40 minutes, 35 minutes, 30 minutes, or less. In certain embodiments of the invention, the food should be ingested within about 30 minutes of administration of one or both of component (a) and component (b). In certain embodiments of the invention, one or both of component (a) and component (b) is administered without food. In certain embodiments of the invention, the food is administered for a period of about 45 minutes, such as at least about any of about 50 minutes, 55 minutes, 1 hour, 1.25 hours, , 1.5 hours, 1.75 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or more. In certain embodiments of the present invention, the food should not be ingested within about one hour of administration of one or both of component (a) and component (b).

In certain embodiments of the invention, one or both of component (a) and component (b) are administered before or after the food. In certain embodiments of the present invention, one or both of component (a) and component (b) is at least about 30 minutes of food, such as about 40 minutes, 45 minutes, 50 minutes, 55 minutes, , 1.5 hours, 1.75 hours, 2 hours, 3 hours, 4 hours, or 5 hours, or at least about 30 minutes, such as at least about 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1.25 hours , 1.5 hours, 1.75 hours, 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, 4 hours, or 5 hours. In certain embodiments of the invention, one or both of component (a) and component (b) are administered at least one hour before food or two hours after food.

In certain embodiments of the invention, one or both of component (a) and component (b) are administered prior to the food. In certain embodiments of the invention, the food is administered within about 2 hours prior to administration of one or both of component (a) and component (b), such as any of about 1.5 hours, 1.25 hours, 1 hour, 55 minutes, Within about 2 hours after administration of one or both of component (a) and component (b), for example, within about 1.5 hours, for example, within 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, , 1.25 hours, 1 hour, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, or less.

In certain embodiments of the invention, the food is high in fat and / or calories. In certain embodiments of the invention, the food is at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% Lt; / RTI >

In certain embodiments of the invention, the bacterial infection is associated with a Gram-positive or Gram-negative bacteria. In certain embodiments of the invention, the bacteria is enterobacteriaceae. Bacteria Acinetobacter (Acinetobacter), Bello Vibrio (Bellovibrio), Burke holde Liao (Burkholderia), chlamydia (Chlamydia), Enterobacter (Enterobacter), Escherichia (Escherichia), Fran when cellar (Francisella), Haemophilus (Haemophilus), Helicobacter pylori (Helicobacter), keulrep when Ella (Klebsiella), Leo not Nella (Legionella), morak Cellar (Moraxella), Neisseria (Neisseria), O (Pantoea), Pseudomonas (Pseudomonas) in the panto, Salmonella (Salmonella ), and Stella O troponin Pseudomonas (Stellaotrophomonas), Vibrio (Vibrio), or Yersinia (Yersinia). In certain embodiments of the invention, the bacteria are selected from the group consisting of Citrobacter freundii ), Enterobacter aerogenes , Enterobacter cloacae , Escherichia coli , Klebsiella pneumoniae , or Klebsiella oxytoca . In certain embodiments of the invention, the bacterium is E. coli. In certain embodiments of the invention, the bacteria is Klebsiella pneumoniae. In certain embodiments of the present invention, bacteria Burke holde Ria Malayan (Burkholderia mallei), Burke holde Ria pseudo Malayan (Burkholderia pseudomallei , Francisella tularensis or Yersinia pestis ). In certain embodiments of the invention, the bacteria have been genetically engineered.

In certain embodiments of the invention, the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter-related blood infection, secondary blood infection with UTI cause, neonatal sepsis, , Otitis media, or wound infection. In certain embodiments of the invention, the bacterial infection is selected from the group consisting of recurrent UTI, complex UTI, simple UTI, bacteremia UTI, acute pyelonephritis, hospital-acquired pneumonia, community acquired pneumonia, respiratory- (cIAI), or bronchitis. In certain embodiments of the invention, the bacterial infection is UTI. In certain embodiments of the invention, the bacterial infection is complex UTI (cUTI). In certain embodiments of the invention, the cUTI may be administered in combination with one or more of the following agents selected from the group consisting of urinary retention, urinary catheterization, structural or anatomical abnormalities of the urinary tract, and neurological deficits resulting in at least 100 mL of residual urine It is related to the argument. In certain embodiments of the invention, the bacterial infection is acute pyelonephritis.

In certain embodiments of the invention, the bacteria express magnified-spectrum beta-lactamase (ESBL). The sequence and classification of ESBLs is known to the ordinarily skilled artisan. For example: Babic et al. Drug Resistance Updates, 2006, 9: 142-156; Bush et al. Antimicrob Agents Chemother, 2010; 54 (3): 969-976). Also see The Lactamase Engineering database (www.laced.uni-stuttgart.de/; www.lahey.org/Studies/).

In certain embodiments of the present invention, the ESBL is inhibited by component (b). In certain embodiments of the invention, the ESBL is an Ambler Class A ESBL. In certain embodiments of the invention, the ESBL is or is believed to be CTX-M, TEM, or SHV beta-lactamase. In certain embodiments of the invention, the TEM beta-lactamase comprises at least one amino acid substituent selected from R164S / H / C, G238D / N / S, and E104K. In certain embodiments of the invention, the SHV beta-lactamase comprises at least one amino acid substituent selected from D179A / N / G, G238S / A, and E240K. In certain embodiments of the invention, the ESBL is CTX-M group 1, 2, 8, 9, or 25. In certain embodiments of the present invention, the ESBL is selected from the group consisting of CTX-M, CTX-M-1, CTX-M-2, CTX-M-3, CTX- CTX-M-5, CTX-M-5, CTX-M-5, CTX-M-6, CTX-M-7, CTX- M-14, CTX-M-15, CTX-M-16, CTX-M-17, CTX-M-19, CTX- KLUA-5, CTX-M-24, CTX-M-24, CTX-M-25, CTX-M-26, CTX- KLUA-6, KLUA-8, KLUA-9, KLUA-10, KLUA-11, KLUG-1, SHV-2, SHV-7, SHV-12, TEM-1 or TOHO-1. In certain embodiments of the present invention, the ESBL is selected from the group consisting of CTX-M-1, CTX-M-3, CTX-M-14, CTX-M-15, CTX-M-55, SHV- 12, or TEM-1, respectively. In certain embodiments of the invention, the ESBL is CTX-M-14 or CTX-M-15, or CTX-M-14 or CTX-M-15. In certain embodiments of the invention, the ESBL is CTX-M-14. In certain embodiments of the invention, the ESBL is CTX-M-15.

In certain embodiments of the invention, the bacteria further express one or more additional beta-lactamases. In certain embodiments of the invention, the bacteria further express a TEM wild type or SHV wild type.

In certain embodiments of the invention, the bacteria further express one or more additional ESBLs. In certain embodiments of the invention, the one or more additional ESBLs are each CTX-M, TEM, or SHV beta-lactamase. In one particular embodiment of the invention, one or more additional ESBLs are selected from the group consisting of CTX-M, CTX-M-1, CTX-M-2, CTX-M-3, CTX- M-14, CTX-M-15, CTX-M-16, CTX-M-17, CTX-M-12, , CTX-M-19, CTX-M-20, CTX-M-21, CTX-M-22, CTX-M-23, CTX-M- 1, KLUA-5, KLUA-6, KLUA-8, KLUA-9, KLUA-10, KLUA-11, KLUG-1, SHV-2 , SHV-7, SHV-12, TEM-1, or TOHO-1. In certain embodiments of the present invention, one or more additional ESBLs are selected from the group consisting of CTX-M-1, CTX-M-3, CTX-M-14, CTX-M-15, SHV-2, SHV- TEM-1 < / RTI >

Methods for determining the expression of ESBL or beta-lactamase are well known in the art to which this invention pertains. In some embodiments of the invention, the method of detecting an ESBL comprises a phenotype that uses the growth of bacteria in a medium supplemented with different types of beta-lactam antibiotics, such as antibiotics. In certain embodiments of the invention, the expression of ESBLs can be detected using conventional PCR, real-time PCR, next generation sequencing, genomic sequencing such as Lumine xMAP technology, DNA microarrays such as CHECK-MDR CT101, CT102, CT103, or CT103XL -Points, The Netherlands). ≪ / RTI > ESBL expression can also be determined by detecting the protein using antibody assays or mass spectrometry. In some cases, the enzyme may be designed to identify a particular gene, such as a CTX-M-14 analog or a CTX-M-15 analog, but may not distinguish it from other genes with high sequence identity in the region or region being detected , And are identified by CTX-M analogs when identified by analysis, such as specific gene based assays. Methods for detecting ESBL-producing bacteria are disclosed in U.S. Published U.S. Patent Nos. US2013 / 0065790; Frickmann et al. (2014) Biomed Research International, Article ID 375681; And Souverein et al. (2017) Journal of Antimicrobial Chemotherapy, doi: 10.1093 / jac / dkx189.

In certain embodiments of the invention, the bacteria have an antibiotic resistance phenotype. Methods for determining the antibiotic resistance phenotype are well known in the art. In certain embodiments of the invention, the antibiotic resistance phenotype can be determined by analyzing a minimal inhibitory concentration or minimum bactericidal concentration (MBC). In certain embodiments of the invention, the antibiotic resistance phenotype is resistance to a combination of a DHFR inhibitor, a sulfonamide, an anaerobic DNA inhibitor, a fluoroquinolone, a beta-lactam, or a beta-lactam: beta-lactamase inhibitor. In certain embodiments of the invention, the antibiotic resistance phenotype is resistance to a combination of fluoroquinolone, beta-lactam or beta-lactam: beta-lactamase inhibitor. In certain embodiments of the invention, the antibiotic resistance phenotype is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, sepracur, cephadoxil, cephem, cechimycin, ceftibuten, Ciprofloxacin, pinafloxacin, gentamycin, imipenem, ciprofloxacin, ciprofloxacin, pinafloxacin, ciprofloxacin, pinafloxacin, ciprofloxacin, ceftazidime, ceftazidime, ceftriaxone, , Levofloxacin, loracabef, mecillinam, meropenem, nitrofurantoin, piperacillin, or tobramycin. In certain embodiments of the invention, the antibiotic resistance phenotype is ST131.

In certain embodiments of the invention, the bacteria express the qnr gene. In certain embodiments of the present invention, qnr gene is a member of the qnr A, qnr B, qnr C , qnrD, qnr S, or qnrVC family.

In certain embodiments of the invention, the bacteria do not express carbapenemase. In certain embodiments of the invention, the bacteria do not express the Ambler class C ESBL. In certain embodiments of the invention, the bacterium does not express a protein selected from the group consisting of AmpC, KPC, OXA, NDM, or OMP. In certain embodiments of the invention, the bacteria do not express AmpC. In certain embodiments of the invention, the bacteria do not express transferable AmpC. In certain embodiments of the invention, the bacteria do not express KPC. In certain embodiments of the invention, the bacteria do not express OXA. In certain embodiments of the invention, the bacteria do not express OXA-48 or OXA-181. In certain embodiments of the invention, the bacteria do not express NDM. In certain embodiments of the invention, the bacteria do not express NDM-1. In certain embodiments of the invention, the bacteria do not express OMP. In certain embodiments of the present invention, the bacteria do not express carbapenemase or transcribable AmpC. In certain embodiments of the invention, the bacteria are selected from the group consisting of KPC, NDM-1, ACC, ACT / MIR, CMYI / , DHA, or FOX.

In some embodiments of the invention, component (a) and component (b) are administered with at least one additional antibiotic. In some embodiments of the invention, the additional antibiotic is administered by mucosal, oral, or parenteral administration. In some embodiments of the invention, the additional antibiotic is administered intravenously. In some embodiments of the invention, the additional antibiotic is administered orally. In some embodiments of the invention, the additional antibiotic is a beta-lactam, such as a penicillin derivative, cephalosporin, monobactam, or carbapenem. In some embodiments of the invention, the additional antibiotic is selected from the group consisting of amoxicillin, ampicillin, aztreonam, sephacler, sephadoxil, cephem, sephycin, ceftibuten, cefdinir, cefditoren, , Cephrozil, ceftazidime, ceftriaxone, sefroxime, cepharaxine, cephradine, doripenem, gentamycin, imipenem, loracabef, meropenem, piperacillin, ticarcillin ticarcillin, or tobramycin. In some embodiments of the invention, additional antibiotics are formulated with component (a). In some embodiments of the invention, an additional antibiotic is formulated with component (b).

In some embodiments of the invention, the IC ₅₀ of component (a) is at least about 50 μM, such as about 100 μM, 200 μM, 300 μM, 400 μM, 500 μM, 600 μM, 700 μM, 800 μM, 900 μM, or 1000 μM or more for ESBL. In certain embodiments of the invention, the IC ₅₀ of component (a) is about 100 μM or greater than 1000 μM. In some aspects of the invention, half of the maximal inhibitory concentration (IC ₅₀ ) is a measure of the efficacy of a substance in inhibiting a particular biological or biochemical function. In some aspects of the invention, the IC ₅₀ is a quantitative measure that indicates the amount of inhibitor required to halve a given biological process or factor of a process such as an enzyme, cell, cell receptor or microorganism. Methods for measuring IC ₅₀ in vitro and in vivo are known in the art.

In some embodiments of the invention, the K _M of component (a) is at least about 30 _μM for ESBL, eg about 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM or more for ESBL. In certain embodiments of the invention, the K _M of component (a) is at least about 100 μM for ESBL. In some aspects of the invention, K _M is the substrate concentration at which the reaction rate is half the maximum rate achieved by the system at the saturated substrate concentration. Methods for measuring K _M in vitro and in vivo are known in the art.

In certain embodiments of the invention, administration of components (a) and (b) in accordance with the provided methods may be carried out with a composition that is greater than 30%, such as greater than about 35%, 40%, 45%, 50% a). < / RTI > In certain embodiments of the invention, administration of components (a) and (b) in accordance with the provided method is carried out with a composition that is greater than 40% fT> MIC, greater than 50% fT> MIC, or 60% Resulting in systemic exposure of the larger component (a).

In certain embodiments of the present invention, administration of the components (a) and (b) according to the method provided is 20% fT> large, for example, about 25% _{C T, 30%, 35%} , 40%, 50% Resulting in systemic exposure of the larger component (b). In certain embodiments of the present invention, component according to the instructions provided (a) and (b) the administration is 20% fT> greater than C _T, 25% fT> greater than C _T, 30% fT> greater than C _T, Or systemic exposure of component (b) greater than 35% fT > C _T.

In certain embodiments of the invention, the maximum concentration of component (a) is between about 10 ug / mL and about 30 ug / mL, such as between 10 ug / mL and 25 ug / mL, between 15 ug / mL and Between about 30 μg / mL, or between 15 μg / mL and about 25 μg / mL. In certain embodiments of the invention, the maximum concentration of component (b) is between about 0.2 ug / mL and about 5 ug / mL, such as between 0.2 ug / mL and about 4 ug / mL, between about 0.2 ug / mL And between about 3 μg / mL, between about 0.5 μg / mL and about 4 μg / mL, between about 1 μg / mL and about 4 μg / mL, between about 1 μg / mL and about 3 μg / mL. In some embodiments of the invention, the maximum concentration is the maximum blood concentration.

In certain embodiments of the present invention, the PBLIE of component (b) in combination with component (a) can be used for at least about 0.5 hours, such as about 0.75 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 Hour, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, 2.25 hours, 2.5 hours, 2.75 hours, 3 hours, or 3.5 hours or more. In certain embodiments of the present invention, the PBLIE of component (b) in combination with component (a) is at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours. Methods for measuring PBLIE in vitro are known in the art. In some aspects of the present invention, to calculate the PBLIE, the two conditions, such as the first condition in which the bacteria are exposed to? -Lactam alone and the second condition in which they are exposed to the same combination of? -Lactam in combination with? -Lactamase, The experimental conditions are compared. In the assay, after a certain period of time, such as after one hour, the cells are washed and re-suspended in the medium with? -Lactam alone and then the growth of the bacteria is monitored over time. In some embodiments of the invention, the difference between the time it takes two cultures to grow 1-log of the colony forming units per mL after washing (J Antimicrob Chemother 2004; 53: 616-619) defines PBLIE It is the matrix used.

In certain embodiments of the invention, the MIC of component (a) when used in combination with component (b) is less than or equal to about 8 μg / mL, such as less than about 4 μg / mL, less than 2 μg / / mL, 0.5 μg / mL or less, or 0.25 μg / mL or less. In certain embodiments of the present invention, the MIC of component (a) when used in combination with component (b) is less than about 4 ug / mL, less than 2 ug / mL, less than 1 ug / mL, less than 0.5 ug / mL . In certain embodiments of the invention, the MIC of component (a) alone, for example, a bacterial strain, such as an ESBL-producing enterobacteriaceae such as the same microorganism, is greater than about 4 ug / mL, Ug / mL, 16 / / mL, or 32 ㎍ / mL or more. In certain embodiments of the present invention, the MIC of component (a) alone is the same as component (a) when used in combination with component (b) for the same microorganism, such as a bacterial strain, for example an ESBL-producing enterobacteriacease 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 16 times, 32 times, 64 times or more, for example. Methods for measuring MIC in vitro are known in the art.

In a particular embodiment of the invention, the minimum microbicidal concentration (MBC) of component (a) when used in combination with component (b) is less than the MIC of component (a) when used in combination with component (b) Times or twice or more. In certain embodiments of the invention, the minimum bactericidal concentration (MBC) of component (a) when used in combination with component (b) is less than the MIC of component (a) when used in combination with component Or greater.

In another embodiment of the present invention, a method is provided for treating a mammal having a bacterial infection, the method comprising the steps of: a) obtaining a sample from a mammal suffering from a bacterial infection ; b) identifying the presence of the bacteria in said sample; c) determining the MIC required to kill the bacteria identified in step b); And d) administering the combination composition to the subject based on the MIC value determined in step c).

V. Kit  And articles of manufacture

The present disclosure relates to articles or kits comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt or hydrate thereof, to provide. In some embodiments of the invention, the kit comprises (c) an effective amount of components (a) and (b) for use, for example, in accordance with the methods described herein to an individual in need thereof for treating a bacterial infection Lt; RTI ID = 0.0 > a < / RTI > In some embodiments of the invention, the bacterial infection is associated with a bacterium that expresses extended-spectrum beta-lactamase (ESBL).

In certain embodiments of the invention, the kit comprises one or more containers containing component (a) and / or (b). In certain embodiments of the invention, the kit comprises a container comprising component (a), wherein component (a) is cefentibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof. In certain embodiments of the present invention, component (a) comprises a hydrate. In certain embodiments of the present invention, component (a) is ceftuthene dihydrate. In certain embodiments of the present invention, the kit comprises a container comprising component (b), wherein component (b) is clavulanic acid, or a pharmaceutically acceptable salt thereof. In certain embodiments of the invention, component (b) comprises a pharmaceutically acceptable salt. In certain embodiments of the invention, the salt is sodium or potassium. In certain embodiments of the present invention, component (b) is potassium clavulanate. In certain embodiments of the invention, the kit comprises a ceftibuten dihydrate (component (a)), wherein component (a) and component (b) are provided in the same container (e.g., formulated together) And potassium clavulanate (component (b)). In certain embodiments of the invention, the kit comprises a container comprising both component (a) and component (b). In certain embodiments of the invention, the kit comprises a first container comprising component (a) and a second container comprising component (b).

In some embodiments of the invention, the components of the kit and / or kit are packaged in a package containing, for example, paper (e.g., cardboard), plastic or other suitable material. In some embodiments of the invention, the components of the kit are contained in one or more containers. In some embodiments of the invention, the kit further comprises instructions for use in accordance with any of the methods described herein. The instructions provided in the kit are generally written in a label or package insert (e.g., a sheet of paper included in the kit), but machine-readable instructions (e.g., manuals on magnetic or optical storage disks) are also acceptable .

In some embodiments of the invention, components (a) and (b) of the kits provided herein are included as pharmaceutical compositions as described herein. In some embodiments of the present invention, component (a) and component (b) are provided as separate compositions. In some embodiments of the present invention, component (a) and component (b) are provided together in the same composition.

In some embodiments of the invention, the kit contains component (a) and component (b) in combination with component (a) and component (b) in a single dosage form and / or with separate administration of various single dosage forms. In some embodiments of the invention, the single dosage form is an oral dosage form. In some embodiments of the invention, the single dosage form is for administration of a unit dose, for example, in the form of a tablet or capsule, such as a unit dosage form. In some embodiments of the invention, the unit dose is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of active ingredient will generally be equal to the dosage of the active ingredient to be administered to a subject and / or a convenient portion of such a dose, e.g., one-half or one-third of such a dose. The dosage (e.g., mg) and dosage form (e.g., tablets, capsules) of each drug may be any dosage or form as described above.

In some embodiments of the invention, the kit contains at least two dosage forms of component (a), such as two or more portions in unit dosage form. In some aspects of the invention, the two or more dosage forms together comprise a total daily dose, for example, from about 500 mg to 2000 mg, such as from about 800 mg to about 1800 mg, such as the total daily dose, as described above , For example from 900 mg to 1200 mg, of the total daily dose of component (a). In some embodiments of the invention, the kit is administered in combination with a pharmaceutically acceptable excipient or diluent to provide a total daily dosage at a dose of component (a) divided two to five times a day, for example two or three times a day. Administration forms, e. G., Unit dosage forms. In some embodiments of the invention, the dosage form, e.g., unit dosage form, is between about 150-400, 200-400, or 300-400 mg, such as about 300 mg or about 400 mg, 600 mg of component (a). In some embodiments of the present invention, the kit may be formulated as a unit dosage form for administration of two or more unit dosage forms for each divided dose, such as one, two, three, or four unit dosage forms, (a), for example, a unit dosage form. In some embodiments of the invention, dosage forms, such as unit dosage forms, comprise between about 50 and 250 mg, such as about 100 mg or about 200 mg, such as 100 mg and 200 mg. In some embodiments of the present invention, the kit may comprise up to about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, For example, a unit dosage form, to administer a total daily dose for a period of at least 3 days, e. G. 7 to 10 days.

In some embodiments of the invention, the kit contains at least two dosage forms of component (b), such as two or more portions in unit dosage form. In some aspects of the invention, the two or more dosage forms together comprise a total daily dose of, for example, from about 250 mg to about 750 mg, such as from about 375 mg to about 562.5 mg, such as the total daily dose as described above , Sufficient to provide at least one total daily dose of component (b). In some embodiments of the present invention, the kit may comprise one or more doses of component (b) to administer the total daily dose at a dose of component (a) divided two to five times a day, Administration forms, e. G., Unit dosage forms. In some embodiments of the invention, the dosage form, e. G., Unit dosage form, is between about 50-250 mg, 200-400, or 125-187.5 mg, such as component (b) And about 50-250 mg of component (b) which is 187.5 mg. In some embodiments of the present invention, the kit may be formulated as a unit dosage form for administration of two or more unit dosage forms for each divided dose, such as one, two, three, or four unit dosage forms, (b), for example, a unit dosage form. In some embodiments of the invention, dosage forms, such as unit dosage forms, comprise between about 50 and 150 mg, for example, about 62.5 mg or about 125 mg, such as 62.5 mg and 125 mg. In some embodiments of the invention, the kit may be administered for up to about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, For example, a unit dosage form, to administer the total daily dose for a period of at least 3 days, such as 7 to 10 days.

In some embodiments of the present invention, the container may be a divided container, such as a divided bottle or a divided foil pack. In some embodiments of the present invention, component (a) and component (b) are separated from each other in a divided container and / or each dosage form, for example a unit dosage form, is separated from one another in a divided container. The container may be made from a pharmaceutically acceptable material such as a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (e.g., " recharging " Or blister packs having individual capacities for compressing the packs according to a treatment schedule, as is known in the art to which the present invention pertains. The container used may vary depending on the exact dosage form involved. It is feasible that one or more containers are used together in a single package for sale in a single dosage form. For example, the tablets may in turn be contained in one bottle contained within one box.

In some embodiments of the invention, the kit comprises a blister pack. Blister packs are well known in the packaging industry and are used for packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally contain a sheet of relatively stiff material that is preferably covered with a foil of a clear plastic material. During the packaging process, a recess is formed in the plastic foil. The concave portion may have the size and shape of the individual tablets or capsules to be packaged, or may have a size and shape to accommodate multiple tablets and / or capsules to be packaged. In some aspects of the invention, the tablets or capsules are thus disposed in the recessed portion, and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil opposite the direction in which the loose portion is formed. As a result, tablets or capsules are individually sealed or collectively sealed, if necessary, in the concave portion between the plastic foil and the sheet. In some aspects of the invention, the strength of the sheet is to allow tablets or capsules to be removed from the blister pack by manually applying pressure to the recesses such that openings are formed in the sheet at the locations of the recessed portions. The tablets or capsules can then be removed through the opening.

In some embodiments of the invention, the kit comprises a dose suitable for administration over several days, such as up to about a week, a month or three months. In some embodiments of the invention, the kit may be administered for up to about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, For example 3 to 7 days, such as 7 to 10 days. In some embodiments of the invention, the kit is a multi-day pack containing a plurality of divided daily doses. In some aspects of the invention, dosages (e.g., tablets) for each administration (e.g., BID or TID administration) within a multi-day pack may be separated into doses for administration at different times or at different times do.

In certain embodiments of the invention, the kit is in a suitable packaging. Suitable packaging materials include, but are not limited to, vials, bottles, jars, stretchable packaging materials (e.g., sealed Mylar or plastic bags), and the like.

In some embodiments of the invention, the kit comprises instructions for administering the component or composition (s) according to any of the methods provided. In some embodiments of the invention, the instructions specify one or more bacterial strains to be treated, including: ESBLs generated by bacterial strains and / or bacterial strains; The group of patients to be treated; The dosage regimen of the individual for the individual, such as the total daily dose of each component or composition, the number of divided doses of each component or composition, the number of tablets or capsules per divided dose, and / or the number of treatment days.

In some embodiments of the invention, the instructions are selected from the group consisting of Citrobacter freundii , Enterobacter aerogenes , Enterobacter cloacae , Escherichia coli , Klebsiella pneumoniae, A composition or composition of kits for treating bacterial infections caused by or associated with enterobacteriacease strains, such as enterobacteriaceae selected from the group consisting of Klebsiella pneumoniae , Klebsiella pneumoniae , or Klebsiella oxytoca . ). In some embodiments of the invention, the instructions specify components of a kit for treating a bacterial infection described herein, such as multiple urinary tract infections, simple urinary tract infections and acute pyelonephritis.

In some embodiments of the invention, the kit comprises an enterobacteriacease or SHV, TEM or CTX-lactamase inhibitor that expresses or produces an extended-spectrum beta-lactamase (ESBL), including any of those described in accordance with the methods provided herein. RTI ID = 0.0 > and / or < / RTI > bacterial infections associated therewith, induced by a particular type of ESBL, such as M. In some embodiments of the invention, the ESBL is or comprises CTX-M-14 or CTX-M-15. In some embodiments of the invention, one treatment selected or determined to have a bacterial infection that expresses or produces ESBL, such as determined by genomic sequencing, such as PCR, real-time PCR, next generation sequencing, Specifies the entity to be

In some of the embodiments provided herein, the instructions may, in some aspects of the present invention, include components (a) and (b) to be administered, which may be specified for administration in a single dose or divided ) ≪ / RTI >

In some embodiments of the invention, the kit comprises about 500 mg to 2000 mg, such as about 600 to 1800 mg, 600 to 1600 mg, 600 to 1400 mg, 600 to 1200 mg, 600 to 1000 mg, 600 to 900 mg, 600 to 800 mg, 800 mg to 2000 mg, 800 mg to 1800 mg, 800 mg to 1600 mg, 800 mg to 1400 mg, 800 to 1200 mg, 800 to 1000 mg, 800 to 900 mg, 900 1000 mg to 1000 mg, 1000 mg to 1200 mg, 1000 mg to 1000 mg, 1000 mg to 1000 mg, 1000 mg to 1000 mg, 1000 mg to 1000 mg, 1000 mg to 1000 mg, 1200 mg to 1200 mg, 1200 mg to 2000 mg, 1200 mg to 1800 mg, 1200 mg to 1600 mg, 1200 mg to 1400 mg, 1400 mg to 2000 mg, 1400 mg to 1800 mg, 1400 mg to 1600 mg, mg, 1600 mg to 1800 mg, or 1800 mg to 2000 mg of the component (a) is administered to a subject (for example, orally administered). All. In some embodiments of the invention, the kit comprises about 250 mg to 750 mg, such as 250 to 600 mg, 250 to 600 mg, 250 to 500 mg, 250 to 375 mg, 250 to 300 mg, 300 From 500 mg to 500 mg, from 500 mg to 750 mg, from 500 mg to 500 mg, from 500 mg to 500 mg, from 500 mg to 500 mg, from 300 mg to 500 mg, from 300 mg to 500 mg, from 300 mg to 375 mg, To 600 mg, or 600 to 750 mg of component (b) per day. In some embodiments of the invention, the kit comprises a total daily dose of 800-1800 mg, for example 900-1200 mg, and a total daily dose of component (a) and 250-750 mg, for example 375-562.5 mg (B) is administered to an individual (e. G., Orally administered).

In some embodiments of the invention, the instructions include a number of divided doses to be administered to provide a total daily dose of one or both of component (a) and component (b), for example, one or more unit doses (E.g., tablets or capsules). In some embodiments of the invention, the kit may be administered in unit dosage form (e.g., capsules) of component (a) and / or (b) two to five times a day, Includes instructions for. In some embodiments of the invention, components (a) and (b) are formulated separately and the instructions specify that components (a) and (b) are administered simultaneously or in combination at the same time.

In some embodiments of the invention, the kit comprises instructions for providing written memory assistance, wherein the written memory aid comprises information and / or instructions for a physician, pharmacist or other health care provider, For example, in the form of a number next to a tablet or capsule, and the number corresponds to a day of therapy or a card containing information of the same type for which the specified tablets or capsules should be ingested. Other examples of these written memory aids include: "First week, Monday, Tuesday" ... etc ... Second week, Monday, Tuesday ... " It is a calendar printed on. Other variations of memory aiding will be readily apparent. A "daily dose" may be a single tablet or capsule or several tablets or capsules to be ingested on a given day. Where the kit contains an individual composition, the daily dosage of the one or more compositions of the kit may be comprised of one tablet or capsule, while the daily dosage of another one or more compositions of the kit may be in the form of several tablets or capsules Lt; / RTI >

In some embodiments of the invention, the kit comprises a dispenser to be dispensed at one time or a daily dose divided according to the order of their intended use. Optionally, the dispenser is further equipped with a memory-assist device to facilitate the performance of the therapy. An example of such a memory-assist is a mechanical counter, which represents a divided number of dispensed daily doses. Another example of such a memory-assist is a liquid-crystal readout, which reads, for example, the time at which the last daily dose was taken and / or the date at which the last daily dose was ingested and / Or a battery-powered-micro-chip memory coupled to the well-sounded signal.

In some embodiments of the invention, the kit comprises at least one additional antibiotic. In some embodiments of the invention, the additional antibiotic is a beta-lactam, such as a penicillin derivative, cephalosporin, monobactam, or carbapenem. In some embodiments of the invention, the additional antibiotic is selected from the group consisting of amoxicillin, ampicillin, aztreonam, sephacler, sephadoxil, cephem, sephycin, ceftibuten, cefdinir, cefditoren, , Cephrozil, ceftazidime, ceftriaxone, sefroxime, cepharaxine, cephradine, doripenem, gentamycin, imipenem, loracabef, meropenem, piperacillin, ticarcillin , Or tobramycin. In some embodiments of the invention, additional antibiotics are formulated with component (a). In some embodiments of the invention, an additional antibiotic is formulated with component (b). In some embodiments of the invention, the additional antibiotic is suitable for intravenous administration. In some embodiments of the invention, the additional antibiotic is suitable for oral administration. In some embodiments of the invention, the kit may be administered separately (e.g., concurrently, concurrently, or sequentially) in combination with component (a) and / or component (b) by mucosal, oral or parenteral administration, or Together with instructions for administering additional antibiotics.

VI. Illustrative Example

Among the implementations provided herein are:

1. A method of treating an Enterobacteriaceae bacterial infection of an individual comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to said individual,

The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);

A method characterized by at least one of the following (i) to (iii):

(i) component (a) is administered to said individual at a total daily dose of 800-1800 mg;

(ii) component (b) is administered to said individual in a total daily dose of 250-750 mg;

(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day.

2. Enterobacteriaceae of a subject As a method for preventing bacterial infection,

(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,

Orally to the subject,

The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);

A method characterized by at least one of the following (i) to (iii):

(i) component (a) is administered to said individual at a total daily dose of 800-1800 mg;

(ii) component (b) is administered to said individual in a total daily dose of 250-750 mg;

(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day.

3. The method of embodiment 1 or embodiment 2, wherein components (a) and (b) are co-administered with the same pharmaceutical composition.

4. A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual,

(a) orally administering ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, to said individual,

The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);

Component (a) is administered in a total daily dosage of 800-1800 mg and / or in divided doses at least twice per day, wherein the divided dose of component (a) is about 300-400 mg;

Wherein component (a) is administered in combination with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is administered in a total daily dosage of about 250-750 mg and / Wherein the divided dose of component (b) is about 100-250 mg.

5. A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual,

(b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to said individual,

The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);

Component (b) is administered in a total daily dose of 250-750 mg and / or in divided doses more than once a day, wherein the divided dose of component (b) is about 100-250 mg;

Component (b) is administered together with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is administered in a total daily dose of about 800-1800 mg and / Wherein the divided dose of component (a) is about 300-400 mg.

6. The method of any one of embodiments 1-5 wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intra-abdominal infection, otitis media, or wound infection,

Optionally, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infection (cIAI) or community acquired pneumonia (CAP).

7. A method of treating an Enterobacteriaceae bacterial infection of an individual,

(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,

Orally to the subject,

The bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media,

Alternatively, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonia (CAP); And / or

Wherein said bacterial infection is caused or associated with enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL).

8. A method for preventing an Enterobacteriaceae bacteria infection in an individual,

(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,

Orally to the subject,

The bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media,

Alternatively, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonia (CAP); And / or

Wherein said bacterial infection is caused or associated with enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL).

9. A method of treating bacterial infections in an individual,

(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,

Orally to the subject,

Wherein said bacterial infection is caused by enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL), said subject having previously been administered an antibiotic to treat said bacterial infection.

10. The method as in any one of embodiments 1-9, wherein component (a) is cefthuthene dihydrate.

11. The method of any one of embodiments 1 to 10, wherein component (b) is potassium clavulanate.

12. The method according to any one of embodiments 1 to 2 and embodiments 4 to 11, wherein component (a) is administered simultaneously, concurrently, or sequentially with component (b).

13. The method of any one of embodiments 7-12, wherein components (a) and (b) are co-administered with the same pharmaceutical composition.

14. The process as in any one of embodiments 1-13, wherein component (a) is in a ratio of 1: 1 to 7: 1 relative to component (b) To the subject.

15. The method of any one of embodiments 1-14 wherein component (a) is administered to said individual at a ratio of 1: 1 to 3: 1 to component (b).

16. The method of any one of embodiments 7 to 15, wherein the method is characterized by one or more of the following (i) to (iii):

(i) component (a) is administered to said individual at a total daily dose of 800 to 1800 mg;

(ii) component (b) is administered to said individual at a total daily dose of 250-750 mg;

(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day.

17. The method of any one of embodiments 1 to 3, 6 and embodiments 10 to 16, wherein said method is characterized by (i) above, wherein said total daily dose is administered in divided doses at least twice per day How it is.

18. The method of any one of embodiments 1 to 3, 6 and embodiments 10 to 17, wherein said method is characterized by (ii) above wherein said total daily dose is administered in divided doses at least twice per day How it is.

19. The method as in any one of embodiments 1 to 3, 6 and embodiments 10 to 18, wherein the method is characterized by (i), (ii) and (iii) above.

20. The method of any one of embodiments 1-6 and embodiments 10-19, wherein the total daily dose of one or both of the components (a) and (b) is 2-5 divided doses per day ≪ / RTI >

21. The combination of any one of embodiments 1-6 and embodiments 10-20 wherein the total daily dose of one or both of the components (a) and (b) ≪ / RTI >

22. The method of any one of embodiments 1-6 and embodiments 10-21, wherein the divided doses of component (a) are administered in an amount of about 300-600 mg of component (a).

23. The method of any one of embodiments 1-6 and embodiments 10-22, wherein the divided dose of component (a) is about 300-400 mg of component (a).

24. The method of any one of embodiments 1-23, wherein component (a) is administered at a total daily dose of 900-1200 mg.

25. The method of any one of embodiments 1-6 and embodiments 10-24, wherein the divided doses of component (b) are administered in an amount of about 100-250 mg of component (b).

26. The method of any one of embodiments 1-25, wherein component (b) is administered in a total daily dose of 375-562.5 mg.

27. A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual,

(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And

(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,

Orally to the subject,

The bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media,

Alternatively, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonia (CAP); And / or said enterobacteriaceae expressing magnified-spectrum beta-lactamase (ESBL);

(i) the components (a) and (b) are administered in divided doses two or three times a day, wherein the divided dose of component (a) is about 300-400 mg, ) Is about 100-250 mg; And / or

(ii) component (a) is administered at a total daily dose of 900-1200 mg and component (b) is administered at a total daily dose of 375-562.5 mg.

28. The method according to any one of embodiments 1 to 6 and embodiments 10 to 27, wherein the divided administration of component (b) Wherein the amount is about 125-187.5 mg.

29. The method of any one of embodiments 1-6 and embodiments 10-28, wherein the divided dose of component (a) is about 400 mg.

30. The method of any one of embodiments 1-6 and embodiments 10-29, wherein the divided dose of component (a) is about 300 mg.

31. The method of any one of embodiments 1 to 6 and embodiments 10 to 30, wherein the divided doses of component (b) are administered in an amount of about 300 mg.

32. The method of any one of embodiments 1-6 and embodiments 10-31, wherein the divided doses of component (b) are administered in an amount of about 187.5 mg.

33. The method of any one of embodiments 1-32, wherein one or both of components (a) and (b) are formulated into a capsule, a solutab, a sachet, a suspension, Lt; / RTI >

34. The method as in any one of embodiments 1-33, wherein one or both of components (a) and (b) are formulated into a capsule, wherein the capsule is 0, 1, or 2 in size.

35. The method as in any one of embodiments 1-34, wherein one or both of components (a) and (b) are formulated for modified or extended release.

36. The method of any one of embodiments 1-35, wherein said Enterobacteriaceae bacteria are selected from the group consisting of Citrobacter freundii ), Enterobacter aerogenes , Enterobacter cloacae), E. coli (Escherichia coli), keulrep when Ella pneumoniae (Klebsiella pneumoniae , or Klebsiella oxytoca .

37. The method as in any one of embodiments 1-36, wherein said bacterial infection is complex UTI or acute pyelonephritis.

38. The method as in any one of embodiments 1-37, wherein the method is characterized by one or more of the following:

(i) said ESBL is inhibited by component (b);

(ii) the IC ₅₀ of component (a) is greater than about 100 μM or 1000 μM for the ESBL;

(iii) the K _M of the component (a) is greater than about 100 μM for the ESBL;

(iv) administration of the component (a) and component (b) can be carried out with a composition that is greater than 40% f T> MIC, greater than 50% f T> MIC, or greater than 60% f T>a);< / RTI >

(v) administration of the components (a) and (b) is greater than 20% fT > CT, greater than 25% fT > CT, greater than 30% fT > CT, greater than 40% fT > CT Cause systemic exposure of component (b);

(vi) the PBLIE of component (b) in combination with component (a) is at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours;

(vii) when used in combination with component (b), the MIC of component (a) is less than or equal to about 4 ug / mL, less than about 2 ug / mL, less than about 1 ug / mL, ego;

(viii) the MIC of the component (a) alone is about 4-fold higher than the MIC of the component (a) when used in combination with the component (b) against the same enterobacteriaceae, alternatively ESBL-producing enterobacteriaceae Or more;

(ix) when used in combination with component (b), the MBC of component (a) is used in combination with component (b) for the same enterobacteriaceae, optionally ESBL-producing enterobacteriaceae, Is not more than four or two times higher than the MIC of component (a) when used;

(x) The administration of the components (a) and (b) may be such that the maximum concentration of component (a) is between about 10 ug / mL and about 30 ug / mL, between 10 ug / mL and 25 ug / mL, To about 30 [mu] g / mL, or from 15 [mu] g / mL to about 25 [mu] g / mL, optionally the maximum concentration is the maximum serum concentration; And / or

(xi) the maximum concentration of said component (b) is from about 0.2 ug / mL to about 5 ug / mL, from 0.2 ug / mL to 4 ug / mL, from 0.2 ug / mL to about 3 ug / mL, About 4 / / mL, 1 / / mL to about 4 / / mL, 1 / / mL to about 3 / / mL, and optionally the maximum concentration is the maximum serum concentration.

39. The method as in any one of embodiments 1-38, wherein the ESBL is CTX-M, TEM, or SHV beta-lactamase.

40. The method of any one of embodiments 1-39, wherein said ESBL is CTX-M-14 or CTX-M-15 or CTX-M group identical to CTX-M-14 or CTX-M-15.

41. The method as in any one of embodiments 1-40, wherein the bacteria express CTX-M-14.

42. The method as in any one of embodiments 1-141, wherein said bacteria express CTX-M-15.

43. The method as in any one of embodiments 1-42, wherein the bacteria further expresses one or more additional beta-lactamases.

44. The method of embodiment 43, wherein said one or more additional beta-lactamases are independently CTX-M, FEC, KLUA, KLUG, TEM, TOHO, or SHV beta-lactamase.

45. The method of embodiment 43 or 44 wherein said at least one additional beta-lactamase is selected from the group consisting of CTX-M, CTX-M-1, CTX-M-2, CTX- 4, CTX-M-4L or CTX-M-89, CTX-M-5, CTX-M-6, CTX-M-7, CTX- CTX-M-12, CTX-M-13, CTX-M-14, CTX-M-15, CTX-M-16, CTX- M-21, CTX-M-22, CTX-M-23, CTX-M-24, CTX-M-25, CTX- KLUA-1, KLUA-1, KLUA-5, KLUA-6, KLUA-8, KLUA-9, KLUA-10, KLUA-11, KLUG-1, SHV- OSBL, or TOHO-1.

46. The method of any one of embodiments 43 to 45 wherein said at least one additional beta-lactamase is selected from the group consisting of CTX-M-1, CTX-M-3, CTX-M-14, CTX- -2, SHV-7, SHV-12, TEM-1, or TEM-OSBL.

47. The method as in any one of embodiments 1-46, wherein the bacteria has an antibiotic resistance phenotype.

48. The method of embodiment 47, wherein said antibiotic resistance phenotype is resistance to a combination of fluoroquinolone, beta-lactam, or beta-lactam: beta-lactamase inhibitor.

49. The method of embodiment 47 or 48 wherein said antibiotic resistance phenotype is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, cefaclor, cefdroxil, cefepime, cefixime, ceftibuten, cefdinir, cefditoren, cefotaxime, cefpodoxime, Cefprozil, ceftaroline, ceftazidime, ceftriaxone, cefuroxime, cephalexin, cephradine, ciprofloxacin, cephradine, The compounds of the present invention may be used in combination with other therapeutic agents such as ciprofloxacin, doripenem, gentamicin, imipenem, levofloxacin, loracarbef, meropenem, piperacillin, A method which is resistant to tobramycin.

50. The method as in any one of embodiments 47 to 49 wherein said antibiotic resistance phenotype is ST131.

51. The method of any one of embodiments 1-50, wherein the bacterium does not express a protein selected from the group consisting of AmpC, KPC, OXA, NDM, or OMP.

52. The method as in any one of embodiments 1-51, wherein said bacteria do not express AmpC.

53. The method of any one of embodiments 1 to 52, wherein said bacteria do not express KPC.

54. The method of any one of embodiments 1-53, wherein said bacteria do not express OXA.

55. The method of any one of embodiments 1 to 54, wherein said bacteria do not express NDM.

56. The method as in any one of embodiments 1-55, wherein the bacteria do not express OMP.

57. The method of any one of embodiments 1-8 and embodiments 10-56, wherein said subject is previously administered an antibiotic to treat said bacterial infection.

58. The method of embodiment 1 or embodiment 57 wherein said previously administered antibiotic is beta-lactam or fluoroquinolone.

59. The method of any one of embodiments 9 and 57-58, wherein said previously administered antibiotic is not sufficiently effective in treating a bacterial infection.

60. The method of any one of embodiments 9 and 57-59, wherein said previously administered antibiotic is an intravenously administered antibiotic.

61. The method of any one of embodiments 1-60, wherein the administration of components (a) and (b) is a step-down therapy, or an intravenous or oral therapy switch, / RTI >

62. The method of any one of embodiments 1-61, wherein components (a) and (b) are administered with the food.

63. The method of any one of embodiments 1-62, wherein components (a) and (b) are administered without food.

64. The method as in any one of embodiments 1-63, wherein said subject has renal dysfunction.

65. The method as in any one of embodiments 1-64, wherein components (a) and (b) are administered on an outpatient basis and / or self-administered by said individual.

66. The method of any one of embodiments 1-65, wherein components (a) and (b) are at least about or about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.

67. The method of any one of embodiments 1-66, wherein components (a) and (b) are administered for about 7 to 10 days.

68. The method as in any one of embodiments 1-67, wherein the subject is a human.

69. A method for the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection, comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, As an acceptable salt,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

The medicament is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) and component (b) Wherein said divided dose is characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

70. The use as in embodiment 69, wherein component (a) and component (b) are combined in a single dosage form.

71. The use as in embodiment 69, wherein component (a) and component (b) are provided in separate dosage forms.

72. The use of ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

The medicament is used for the oral administration of the divided doses of component (a) to the individual;

Component (a) is administered with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is orally administered in divided doses;

Wherein the components (a) and (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

73. In the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection, (b) the use of clavulanic acid, or a pharmaceutically acceptable salt thereof,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

Said medicament is used for the oral administration of a divided dose of component (b) to a subject;

Component (b) is administered with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is orally administered in divided doses;

Wherein the components (a) and (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

74. A method for the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacteria infection, comprising the steps of: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, As an acceptable salt,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Wherein the components (a) and (b) are formulated for oral administration.

75. The method of embodiment 74, wherein said medicament is used to orally administer a divided dose of component (a) and a divided dose of component (b) to said individual, wherein said component (a) Is administered at a dosage of at least two divided doses per day and the divided dose is characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

76. The use as in embodiment 75 wherein component (a) and component (b) are combined in a single dosage form.

77. The use as in embodiment 75, wherein component (a) and component (b) are provided in separate dosage forms.

78. An enterobacteriaceae bacterial infection for the treatment or prophylaxis of (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a salt,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

The pharmaceutical composition is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) and component (b) Wherein the divided dose is characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

79. The pharmaceutical composition of embodiment 78, wherein component (a) and component (b) are combined in a single dosage form.

80. The pharmaceutical composition according to embodiment 79, wherein component (a) and component (b) are provided in separate dosage forms.

81. A pharmaceutical composition comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the treatment or prevention of an Enterobacteriaceae bacterial infection,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

The pharmaceutical composition is used for the oral administration of divided doses of component (a) to a subject;

Component (a) is administered with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is orally administered in divided doses;

Wherein the component (a) and the component (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

82. A pharmaceutical composition comprising (a) clavulanic acid, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of an Enterobacteriaceae bacterial infection,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

The pharmaceutical composition is used for the oral administration of divided doses of component (b) to a subject;

Component (b) is administered with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is orally administered in divided doses;

Wherein the component (a) and the component (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

83. A method for treating or preventing an Enterobacteriaceae bacterial infection comprising the steps of: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising:

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Wherein said pharmaceutical composition is formulated for oral administration. ≪ RTI ID = 0.0 > 21. < / RTI >

84. The combination of embodiment 83 wherein said composition is used to orally administer a divided dose of component (a) and / or a divided dose of component (b) to said individual, wherein component (a) ) Is administered at a dosage of at least two divided doses per day and the divided dose is characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

85. The pharmaceutical composition according to Embodiment 83 or Embodiment 84, wherein component (a) and component (b) are combined in a single dosage form.

86. The pharmaceutical composition as in any of embodiments 84 or 85, wherein component (a) and component (b) are provided in separate dosage forms.

87. The use or pharmaceutical composition of any one of embodiments 69-86, wherein component (a) is ceftuthene dihydrate.

88. The use or pharmaceutical composition of any one of embodiments 69-87 wherein component (b) is potassium clavulanate.

89. The method of any one of embodiments 69, 71-75, 77, 78, 80-84, and 86-88, wherein component (a) and component (b) In combination or sequential administration.

90. The composition according to any one of embodiments 69, 70, 72, 76, 78, 79, or 89, wherein component (a) ) ≪ / RTI > are administered together.

91. The combination of component (a) and component (b) as described in any one of embodiments 69, 71-75, 77, 78, 80-84 and 86-89, Or a pharmaceutically acceptable salt thereof.

92. The pharmaceutical composition or use of any one of embodiments 69-91, wherein component (a) and component (b) are administered on an outpatient basis and / or self-administered by said individual.

93. The use or pharmaceutical composition as in any one of embodiments 69 to 92, wherein component (a) is administered to said individual at a ratio of 1: 1 to 7: 1 to component (b).

94. The use or pharmaceutical composition as in any one of embodiments 69-93, wherein component (a) is administered to said individual at a ratio of 1: 1 to 3: 1 to component (b).

95. The use or pharmaceutical composition as in any one of embodiments 69 to 94, wherein said divided doses are administered 2-5 times per day.

96. The use or pharmaceutical composition as in any one of embodiments 69-95, wherein said divided doses are administered two to three times per day.

97. The use or pharmaceutical composition of any one of embodiments 69-96, wherein the divided dose of component (a) is 300-600 mg.

98. The use or pharmaceutical composition as in any one of embodiments 69-97, wherein the divided dose of component (a) is 300-400 mg.

99. The use or pharmaceutical composition as in any one of embodiments 69-98, wherein the divided dose of component (a) is about 400 mg.

100. The use or pharmaceutical composition as in any one of embodiments 69-99, wherein the divided dose of component (a) is about 300 mg of component (a).

101. The use or pharmaceutical composition as in any one of embodiments 69-100, wherein the total daily dose of component (a) is from about 900 to 1200 mg.

102. The use or pharmaceutical composition as in any one of embodiments 69-101, wherein the divided dose of component (b) is about 100-250 mg.

103. The use or pharmaceutical composition as in any one of Embodiments 69 to 102, wherein the divided dose of the component (b) is about 125-187.5 mg.

104. The use or pharmaceutical composition as in any one of embodiments 69-103, wherein the total daily dose of component (b) is from about 375 to 562.5 mg.

105. The use or pharmaceutical composition as in any one of embodiments 69 to 104, wherein the divided dose of component (b) is about 125 mg of component (b).

106. The use or pharmaceutical composition as in any one of embodiments 69 to 105, wherein the divided dose of component (b) is about 187.5 mg of component (b).

107. The use or pharmaceutical composition as in any one of embodiments 69-106, wherein one or both of components (a) and (b) are formulated into a capsule, a solution tower, a suspension, a suspension, or a tablet.

108. The use or pharmaceutical composition as in any one of embodiments 69-107, wherein one or both of components (a) and (b) are formulated into a capsule, wherein the capsule is 0, 1, or 2 in size.

109. The use or pharmaceutical composition as in any one of embodiments 69 to 108, wherein one or both of components (a) and (b) are formulated for modified or extended release.

110. The method of any one of embodiments 69 to 109, wherein said Enterobacteriaceae bacteria are Citrobacter freundii ), Enterobacter aerogenes ), Enterobacter cloacae), E. coli (Escherichia coli), keulrep when Ella pneumoniae (Klebsiella pneumoniae , or Klebsiella oxytoca .

111. The use or pharmaceutical composition of any one of embodiments 1-110, wherein said bacterial infection is complex UTI or acute pyelonephritis.

112. The use or pharmaceutical composition of any one of embodiments 69 to 111 wherein said ESBL is CTX-M, TEM, or SHV beta-lactamase.

113. The use or pharmaceutical composition of any one of embodiments 69 to 112 wherein said ESBL is CTX-M-14 or CTX-M-15 or CTX-M group identical to CTX-M-14 or CTX- .

114. The pharmaceutical composition or use as in any one of embodiments 69 to 113, wherein component (a) and component (b) are for use in an individual to which an antibiotic has been previously administered to treat said bacterial infection.

115. The pharmaceutical composition or use of Embodiment 114 wherein said previously administered antibiotic is beta-lactam or fluoroquinolone.

116. The pharmaceutical composition or use according to any one of embodiments 69 to 115, wherein components (a) and (b) are administered together with a food.

117. The pharmaceutical composition or use according to any one of embodiments 69 to 116, wherein components (a) and (b) are administered without food.

118. The pharmaceutical composition or use according to any one of embodiments 69 to 117, wherein said medicament or composition is for use in an individual having impaired renal function.

119. The method of any one of embodiments 69-118, wherein components (a) and (b) are at least about or about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.

120. The pharmaceutical composition or use of any one of embodiments 69 to 119, wherein components (a) and (b) are administered for about 7 to 10 days.

121. The pharmaceutical composition or use as in Embodiments 69 to 120, wherein said subject is human.

122. A pharmaceutical composition comprising (a) at least two oral dosage forms comprising ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and / or (b) a clavulanic acid, or a pharmaceutically acceptable salt thereof, A kit comprising at least two oral dosage forms,

Each dosage form is intended for oral administration of a unit dose to a subject;

At least two oral dosage forms of the component (a) and / or at least two oral dosage forms of the component (b) may contain a divided dose of the component (a) and / or the component (b) more than once a day Wherein component (a) is administered in combination with component (b);

Wherein said divided doses are characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

123. The kit of embodiment 122, wherein component (a) and component (b) are combined in a single dosage form.

124. The kit of embodiment 122, wherein component (a) and component (b) are provided in separate dosage forms.

125. The kit as in any one of embodiments 122-124, further comprising instructions for use of component (a) and component (b).

126. The kit of embodiment 125, wherein the instructions specify that the kit is for use in the treatment or prevention of an Enterobacteriaceae bacterial infection.

127. The method of embodiment 126 wherein said bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, Bacterial infections are a complex urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is enlarged- Kit resulting from enterobacteriaceae expressing lactamase (ESBL).

128. A kit for the treatment or prevention of an Enterobacteriaceae bacterial infection comprising: (a) at least two oral dosage forms comprising ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and / or (b) Or at least two oral dosage forms comprising a pharmaceutically acceptable salt thereof,

Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;

Each dosage form is intended for oral administration of a unit dose to a subject:

At least two oral dosage forms of the component (a) and / or at least two oral dosage forms of the component (b) may contain a divided dose of the component (a) and / or the component (b) more than once a day Wherein component (a) is administered in combination with component (b);

Wherein said divided doses are characterized by one or more of the following:

(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;

(ii) the divided dose of component (a) is at least about 300 mg;

(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or

(iv) the divided dose of component (b) is at least about or at least about 100 mg.

129. The kit of embodiment 128, wherein component (a) and component (b) are combined in a single dosage form.

130. The kit of embodiment 128, wherein component (a) and component (b) are provided in separate dosage forms.

131. The kit as in any one of embodiments 122-130, wherein the kit further comprises instructions for administration of components (a) and (b) to the subject.

132. The kit of embodiment 131, wherein the instructions specify that the divided dosages of components (a) and (b) are for administration together.

133. The kit of embodiment 132, wherein the instructions specify that the divided dosages of components (a) and (b) are for separate administration.

134. The combination of embodiment 131 or embodiment 133, wherein the instructions specify that the divided doses of component (a) and divided doses of component (b) are for simultaneous, concurrent, or sequential administration In kit.

135. The kit as in any one of embodiments 131-134, wherein the instructions specify that the components (a) and (b) are administered on an outpatient basis and / or self-administered by the subject.

136. The kit of embodiments 122-135, wherein said divided doses are administered 2-5 times per day.

137. The kit as in any one of embodiments 122-136, wherein said divided doses are administered two to three times per day.

138. The use as in any one of embodiments 132-137, wherein the instructions specify that the divided doses of component (a) and the divided doses of component (b) are administered 2-5 times per day In kit.

139. The use of any one of embodiments 132-137 wherein the instructions specify that the divided dose of the component (a) and the divided dose of the component (b) are administered two to three times per day. .

140. The kit as in any one of embodiments 122-139, wherein the divided dose of component (a) is 300-600 mg.

141. The kit as in any one of embodiments 122-140, wherein the divided dose of component (a) is 300-400 mg.

142. The kit as in any one of embodiments 122-141, wherein the divided dose of component (a) is about 400 mg of component (a).

143. The kit of embodiments 122-142, wherein the divided dose of component (a) is about 300 mg of component (a).

144. The kit as in any one of embodiments 122-143, wherein the total daily dose of component (a) is from about 900 to 1200 mg.

145. The kit as in any one of embodiments 122-144, wherein the divided dose of component (b) is about 100-250 mg of component (b).

146. The kit as in any one of embodiments 122-145, wherein the divided dose of component (b) is about 125-187.5 mg of component (b).

147. The kit as in any one of embodiments 122-146, wherein the divided dose of component (b) is from about 375 mg to about 532.5 mg.

148. The kit as in any one of embodiments 122-147, wherein the divided dose of component (b) is about 125 mg of component (b).

149. The kit as in any one of embodiments 122-148, wherein the divided dose of component (b) is about 187.5 mg of component (b).

150. The kit as in any one of embodiments 122-149, wherein the oral dosage form comprises a capsule, a solution tower, a suspension, a suspension, or a tablet.

151. The kit as in any one of embodiments 122-150, wherein the oral dosage form is a capsule and the capsule is a size 0, 1, or 2.

152. The kit as in any one of embodiments 122-115, wherein one or both of the oral dosage forms of component (a) and component (b) are formulated for modified or extended release.

153. The kit as in any one of embodiments 122-162, wherein component (a) is ceftuthene dihydrate.

154. The kit as in any one of embodiments 122-143, wherein component (b) is potassium clavulanate.

155. The kit as in any one of embodiments 122-145, wherein component (a) and component (b) are packaged in the same container.

156. The kit as in any one of embodiments 122-155, wherein component (a) and component (b) are packaged in different containers.

157. The method of embodiment 155 or embodiment 156 wherein the container is a divided container and at least two oral dosage forms of the component (a) are separated from one another in the divided container and / Wherein the two oral dosage forms are separated from one another in the divided container.

158. The kit of embodiment 156 or embodiment 157 wherein the container is a blister pack.

159. The method of any one of embodiments 1-68, further comprising administering at least one additional antibiotic.

160. The pharmaceutical composition or use of any one of claims 69 to 121 for use with at least one additional antibiotic.

161. The kit as in any one of embodiments 122-138, wherein the kit comprises at least one additional antibiotic.

162. A method of treating an Enterobacteriaceae bacterial infection of an individual comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to said individual clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein said bacterial infection is associated with an enterobacteriaceae expressing expanded-spectrum beta-lactamase (ESBL) Wherein the bacterial infection is urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection.

163. A method of treating a bacterial infection of an individual, comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; Or CTX-M-15 or CTX-M-14 or CTX-M-15, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, -M-15 is associated with a bacterium that expresses an expanded-spectrum beta-lactamase (ESBL).

164. A method of treating a bacterial infection of an individual, comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to said individual clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein said bacterial infection is associated with or is associated with a bacterium expressing an extended-spectrum beta-lactamase (ESBL) Wherein the subject has previously been administered an antibiotic to treat a bacterial infection.

165. A method of treating a bacterial infection of an individual, comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) administering to said individual clavulanic acid, or a pharmaceutically acceptable salt thereof, wherein component (a) is administered simultaneously, concurrently, or sequentially with component (b) Is associated with or caused by a bacterium expressing an ESBL, characterized by one or more of the following (i) to (iii):

(i) component (a) is administered to a subject in a total daily dose of 800-1800 mg;

(ii) component (b) is administered to a subject in a total daily dose of 250-750 mg;

(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day.

166. The method of any one of embodiments 1-68, embodiment 159, and embodiments 162-165, wherein component (a) is ceftuthene dihydrate.

167. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-166, wherein component (b) is potassium clavulanate.

168. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-167, wherein one or both of components (a) and (b) are administered orally.

169. The method according to any one of embodiments 1-68, embodiment 159 and embodiments 162-16, wherein component (a) is administered simultaneously, concurrently, or sequentially with component (b).

170. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-169, wherein components (a) and (b) are co-administered with the same pharmaceutical composition.

171. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-170 wherein component (a) is administered to said individual at a ratio of 1: 1 to 7: 1 to component (b) .

172. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-171, wherein component (a) is administered to said individual at a ratio of 1: 1 to 3: 1 to component (b) .

173. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-172, wherein the method is characterized by one or more of the following (i) to (iii):

(i) component (a) is administered to said individual at a total daily dose of 800 to 1800 mg;

(ii) component (b) is administered to said individual at a total daily dose of 250-750 mg;

(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day.

174. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiment 173, characterized in that said total daily dose is administered in divided doses more than once per day ≪ / RTI >

175. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiments 173-174, wherein the method is characterized by (ii), wherein the total daily dose is divided more than once per day RTI ID = 0.0 > administered < / RTI >

176. The method of any one of embodiments 1-68, embodiment 159, embodiment 165 and embodiments 173-175, wherein the method is characterized by (i), (ii) and (iii) above.

177. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiments 173-176, wherein the total daily dose of one or both of the components (a) and (b) -5 < / RTI > divided doses.

178. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiments 173-177, wherein the total daily dose of one or both of components (a) and (b) Lt; RTI ID = 0.0 > divided doses. ≪ / RTI >

179. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiments 173-178, wherein each divided dose of component (a) comprises about 300-600 mg of component (a) How to do it.

180. In any one of embodiments 1-68, embodiments 159, embodiment 165, and embodiments 173-179, each divided dose of component (a) comprises about 400 mg of component (a) / RTI >

181. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiments 173-180, wherein each divided dose of component (b) comprises about 100-250 mg of component (b) How to do it.

182. The method of any one of embodiments 1-68, embodiment 159, embodiment 165, and embodiments 173-181, wherein each divided dose of component (b) comprises about 125 mg of component (b) / RTI >

183. A pharmaceutical composition according to any one of embodiments 1-68, embodiment 159, embodiment 165 and embodiments 173-182 wherein each divided dose of component (b) comprises about 187.5 mg of component (b) / RTI >

184. The process of any one of embodiments 1-68, embodiment 159, and embodiments 162-183, wherein one or both of components (a) and (b) is in the form of a capsule, a solution tower, a suspension, ≪ / RTI >

185. The method of any one of embodiments 1-68, embodiment 159, and embodiments 162-184, wherein one or both of components (a) and (b) are formulated together.

186. The method of any one of embodiments 1-68, embodiment 159, embodiments 162-185, wherein one or both of components (a) and (b) are formulated into a capsule, 2 size.

187. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-186 wherein one or both of components (a) and (b) are formulated for modified or extended release .

188. The method of any one of embodiments 1 to 68, embodiment 159, and embodiments 162 to 187, wherein said bacteria is an enterobacteriaceae.

189. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-188 , wherein the bacteria is selected from the group consisting of Citrobacter freundii), Enterobacter aero Jeans (Enterobacter aerogenes), Enterobacter claw ACCA (Enterobacter cloacae), Escherichia coli (Escherichia coli , Klebsiella pneumoniae , or Klebsiella oxytoca .

190. The method of any one of embodiments 1-68, embodiments 159 and embodiments 163-189, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter- , Intraperitoneal infection, otitis media, or wound infection.

191. The method of any one of embodiments 1-68, embodiments 159 and 162-190, wherein said bacterial infection is selected from the group consisting of recurrent UTI, complex UTI, simple UTI, bacteremic UTI, acute pyelonephritis, Wherein the method is hospital-acquired pneumonia, ventilator-acquired pneumonia, or bronchitis.

192. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-191, wherein said ESBL is inhibited by component (b).

193. The method of any one of embodiments 1-68, embodiment 159, embodiment 162 and embodiments 164-192, wherein said ESBL is CTX-M, TEM, or SHV beta-lactamase.

Wherein the ESBL is CTX-M-14 or CTX-M-15, or CTX-M-14 or CTX-M-15. 19. The method of any one of embodiments 1-68, Lt; RTI ID = 0.0 > M-15. ≪ / RTI >

195. The method of any one of embodiments 1-68, embodiment 159, and embodiments 162-194, wherein said bacteria express CTX-M-14.

196. The method of any one of embodiments 1-68, embodiment 159, and embodiments 162-195, wherein said bacteria express CTX-M-15.

197. The method of any one of embodiments 1-68, embodiment 159, and embodiments 162-196, wherein the bacteria further expresses one or more additional beta-lactamases.

198. The method of embodiment 197 wherein said at least one additional beta-lactamase is independently CTX-M, FEC, KLUA, KLUG, TEM, TOHO, or SHV beta-lactamase.

199. The method of embodiment 197 or embodiment 198 wherein said at least one additional beta-lactamase is selected from the group consisting of CTX-M, CTX-M-1, CTX-M-2, CTX- 4, CTX-M-4L or CTX-M-89, CTX-M-5, CTX-M-6, CTX-M-7, CTX- CTX-M-12, CTX-M-13, CTX-M-14, CTX-M-15, CTX-M-16, CTX- M-21, CTX-M-22, CTX-M-23, CTX-M-24, CTX-M-25, CTX- KLUA-1, KLUA-1, KLUA-5, KLUA-6, KLUA-8, KLUA-9, KLUA-10, KLUA-11, KLUG-1, SHV- OSBL, or TOHO-1.

200. The method of any one of embodiments 197-199 wherein said one or more additional beta-lactamases are independently selected from the group consisting of CTX-M-1, CTX-M-3, CTX-M-14, CTX- -2, SHV-7, SHV-12, TEM-1, or TEM-OSBL.

201. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-200 wherein said bacteria has an antibiotic resistance phenotype.

202. The method of embodiment 201 wherein said antibiotic resistant phenotype is resistance to a combination of fluoroquinolone, beta-lactam, or beta-lactam: beta-lactamase inhibitor.

203. The method of embodiment 201 or embodiment 202 wherein said antibiotic resistance phenotype is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, cefaclor, cefdroxil, cefepime, cefixime, ceftibuten, cefdinir, cefditoren, cefotaxime, cefpodoxime, Cefprozil, ceftaroline, ceftazidime, ceftriaxone, cefuroxime, cephalexin, cephradine, ciprofloxacin, cephradine, The compounds of the present invention may be used in combination with other therapeutic agents such as ciprofloxacin, doripenem, gentamicin, imipenem, levofloxacin, loracarbef, meropenem, piperacillin, A method which is resistant to tobramycin.

204. The method as in any one of embodiments 201-203, wherein said antibiotic resistance phenotype is ST131.

205. The method according to any one of embodiments 1-68, embodiment 159 and embodiments 162-204, wherein the bacterium does not express one protein selected from the group consisting of AmpC, KPC, OXA, NDM, or OMP Way.

206. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-205, wherein said bacteria do not express AmpC.

207. The method of any one of embodiments 1-68, embodiment 159, and embodiments 162-206, wherein said bacteria do not express KPC.

208. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-207, wherein said bacteria do not express OXA.

209. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-208, wherein said bacteria do not express NDM.

210. The method of any one of embodiments 1-68, embodiment 159 and embodiments 162-209, wherein the bacteria do not express OMP.

211. The method of any one of embodiments 1 to 68, embodiment 159, embodiment 162, embodiment 163, and embodiments 165 to 210, wherein the subject has previously been administered an antibiotic to treat a bacterial infection .

212. The method of embodiment 164 or embodiment 211 wherein said previously administered antibiotic is beta-lactam or fluoroquinolone.

213. The method of embodiment 212 wherein said previously administered antibiotic is a penicillin derivative, cephalosporin, monobactam, or carbapenem beta-lactam.

214. The method of embodiment 212 or embodiment 213 wherein said previously administered antibiotic is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, sepracur, cephadoxil, cephipim, Ceftazidime, ceftriaxone, sefroxine, cepharaxine, cephradine, doripenem, gentamycin, imipenem, ceftazidime, ceftazidime, , Levofloxacin, loracabef, meropenem, piperacillin, or tobramycin beta-lactam.

215. The method as in any one of embodiments 212-214, wherein the previously administered antibiotic is beta-lactam administered with a beta-lactamase inhibitor.

216. The method of embodiment 215 wherein said previously administered beta-lactamase inhibitor is clavulanate, tazobactam, avibactam, or sulbactam.

217. The method of embodiment 216, wherein said previously administered antibiotic is levofloxacin or fluoroquinolone, which is ciprofloxacin.

218. The method of any one of embodiments 164 and embodiments 212-217, wherein said previously administered antibiotic is not sufficiently effective in treating a bacterial infection.

219. The method of any one of embodiments 164 and embodiments 212-218, wherein said previously administered antibiotic is an intravenously administered antibiotic.

220. The method of any one of embodiments 1-68, embodiments 159 and embodiments 162-219, wherein components (a) and (b) are administered orally and the oral administration of components (a) and (b) Which is a step-down therapy or an oral part of a therapy switch orally within the vein.

221. A pharmaceutical composition comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and a bacterial infection are associated with a bacterium expressing an extended-spectrum-beta-lactamase (ESBL); And (c) instructions for performing the methods of any one of embodiments 1-68, embodiments 159, and embodiments 162-220.

222. A pharmaceutical composition comprising: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and a bacterial infection are associated with a bacterium expressing an extended-spectrum-beta-lactamase (ESBL); (A) and (b) associated with a bacterium expressing an expanded-spectrum-beta-lactamase (ESBL), in order to treat a bacterial infection in a subject in need thereof, A kit comprising instructions for administering an effective amount.

It should be understood that the details of the above-described implementations provided for the purposes of illustration are not to be construed as limiting the scope of the invention. Although some embodiments of the present invention have been described in detail above, those of ordinary skill in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of the invention. Accordingly, all such modifications are intended to be included within the scope of the present invention as defined in the following claims and any equivalents thereof. In addition, although many implementations may be possible that do not achieve all of the advantages of some implementations, particularly preferred implementations, the absence of any particular advantage should not be construed as necessarily to imply that such implementations are outside the scope of the present invention. .

Figures 1A-1F show CTB combined with clavulanate (CLA) at concentrations 2, 4, and 8 times higher than the time-dependent death and minimal inhibitory concentration (MIC) of ceftibuten (CTB) . For cultures treated with ceftibutene alone, the concentration was four times higher than the MIC of the ceftibuten-clavulanate combination. Meropenem (MEM) was included as an 8-fold higher comparator than MIC. Figure IA shows the results for E. coli AECO1156 strains expressing CTX-M-15 and TEM-OSBL. Figure IB shows the results of E. coli AECO1157 expressing CTX-M-15 and TEM-OSBL. Figure 1C shows the results of E. coli AECO1162 expressing CTX-M-14. Figure 1D shows the results for E. coli AECO1166 expressing SHV-12. Figure 1E shows the results for Klebsiella pneumonia AKPN1159 expressing SHV-12. Figure 1F shows the results for Klebsiella pneumonia AKPN1162 expressing CTX-M-15 and SHV-12.
Figure 2 shows that CTX-M, TEM, or SHV ESBLs inhibited at each concentration by ceftibuten alone, a 2: 1 ratio of cetethbutene: clavulanate, and a 2: 1 ratio of amoxicillin: clavulanate The percentage of isolates in the 379 Escherichia coli or Klebsiella pneumoniae isolate genotype panel is shown.
Figure 3 shows the mean plasma concentration-time curve of ceftibuten and metabolite cefotibuten-diesel in healthy male subjects after oral administration of 200, 400, and 800 mg single oral doses of ceftibuten (n = 12 healthy volunteers per dose level) (Antimicrob Agents Chemother 1995; 39: 359-361).
Figures 4A-C are graphs showing the effect of Cefotubentin + KLa on the Escherichia coli isolate AECO1078 with MIC = 32 [mu] g / mL for ceftibutene alone and 1 [mu] g / mL for ceftibuten + clavulanate (2: (PBLIE) of beta-lactamase inhibitor of cefixime + clavulanate (Fig. 4A), cefixime + clavulanate (Fig. 4B) and cefpodocin + clavulanate (Fig. 4C). The change in bacterial growth plotted on the linear graph is expressed as colony forming units (CFU) per mL on the log longitudinal axis relative to the time on the abscissa. After one hour, the medium was changed and replaced with a fresh medium. Four groups are shown in terms of the content of the medium before / after the change in the time shown in the comment. Abbreviations: abx, antibiotics; CTB, cetethibuten; CLA, clavulanate; CFM, Cetixim; CPD, Cefpotism.
Figures 5A-C are graphs depicting the effect of cefcitabine plus clavulanate (Fig. 5A), cefixime plus clavulanate (Fig. 5B) and cefpotamine plus clavulanate (Fig. 5C) on E. coli isolate AECO1157 (PBLIE) after administration of a tamarase inhibitor. The change in bacterial growth plotted on the linear graph is expressed as colony forming units (CFU) per mL on the log longitudinal axis relative to the time on the abscissa. After one hour, the medium was changed and replaced with a fresh medium. Four groups are shown in terms of the content of the medium before / after the change in the time shown in the comment. Abbreviations: abx, antibiotics; CTB, cetethibuten; CLA, clavulanate; CFM, Cetixim; CPD, Cefpotism.
Figures 6A-C are graphs showing the effect of cefcitabine plus clavulanate (Fig. 6A), cefixime plus clavulanate (Fig. 6B) and cefpotamine plus clavulanate (Fig. 6C) on the E. coli isolate APKN1159 (PBLIE) after administration of a tamarase inhibitor. The change in bacterial growth plotted on the linear graph is expressed as colony forming units (CFU) per mL on the log longitudinal axis relative to the time on the abscissa. After one hour, the medium was changed and replaced with a fresh medium. Four groups are shown in terms of the content of the medium before / after the change in the time shown in the comment. Abbreviations: abx, antibiotics; CTB, cetethibuten; CLA, clavulanate; CFM, Cetixim; CPD, Cefpotism.
Figure 7A shows a model Kane moss taeteu f T> MIC E _max exposure response model for (0.25 ㎍ / mL) of the three-butene Petit for E. coli ATCC 25922 in (chemostat model). Figure 7B shows a three Petit butene + clavulanate f T> MIC E _max exposure response model for (1 ㎍ / mL) for the E. coli clinical isolates from Kane moss taeteu model.
Figure 8 shows a simulated graph of the percentage of residual cephalosporin over time generated from the measured kinetic constants.
Figure 9A shows plasma concentrations of ceftibuten at 34.5 mg / kg ceftibuten alone or at various time points following oral administration of 34.5 mg / kg ceftibuten plus 10.8 mg / kg clavulanate. Figure 9B shows the plasma concentration of clavulanate at various time points following oral administration of 10.8 mg / kg clavulanate or 34.5 mg / kg ceftibuten plus 10.8 mg / kg clavulanate. For each treatment group n = 6.
FIGS. 10A-10C are photographs showing the kidney (FIG. 10A), bladder (FIG. 10B), and kidney of mice treated with ceftibuten or ceftibuten + clavulanate in infected mouse UTI models using E. coli CTX- Represents the average log ₁₀ CFU count from urine (Figure 10C).
The present invention can be better visualized with reference to the following description. It is to be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the invention. These and other aspects of the present invention will become apparent to those skilled in the art to which the present invention pertains. These and other implementations of the invention are further described by the following detailed description.

VII. Example

The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

Example  One: ESBL - Escherichia coli having a phenotype Separation  In vitro microbial activity of approved antibiotic panel

A monitoring program for modern E. coli isolates with an ESBL-producing phenotype was performed to assess the microbial activity of approved antibiotic panels in the United States. Microbial activity was determined using the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. As shown in Table 1, the MIC ₉₀ is a mixture of cephalosporins (ceftazidime and ceftriaxone), trimethoprim / sulfamethoxazole, and fluoroquinolone exceeds the breakpoint for susceptibility to fluoroquinolone (levofloxacin).

Table 1. ESBL - Escherichia coli having a phenotype Separation  In vitro microbial activity of approved antibiotic panel

Example  2: Cephalosporin  And? Lactamase  Evaluation of inhibitor combinations

A. Cephalosporin and  β- Lactamase  Early in the inhibitor combination MIC  evaluation

There are a number of generations of oral-bioavailable 12 cephalosporins sold: cephalexin, cefadroxil, cephradine, cefaclor, Cefuroxime, loracarbef, cefprozil, cefdinir, cefixime, ceftibuten, cefpodoxime and cefditoren (see, for example, cefditoren). Initial evaluations described herein focused on orally-bioavailable third-generation cephalosporins, cetearmin, ceftibuten and cephalosporins due to their improved activity spectrum against Gram-negative pathogens. No third-generation cephalosporin cefditoren was tested initially.

The in vitro activity of the oral-bioavailable third generation cephalosporin ceftibuten, cephofoxin and cefixime and the fourth generation cephalosporin cefepime allows the single inhibition concentration (MIC) (MIC) of combinations with one or both of the beta-lactamase inhibitors sold, clavulanate and tazobactam, which are commercially available. For comparison, the MICs of clavulanate alone, tazobactam alone, amoxicillin plus clavulanate and piperacillin plus tazobactam were also measured. Clavulanate was tested with a fixed 2: 1 ratio (cephalosporin: beta-lactamase inhibitor) according to the method used to test clavulanate with amoxicillin; Testosterone bactam was tested at a fixed concentration of 4 μg / mL, such as that performed in combination with piperacillin (CLSI M100-S25, performance criteria for antimicrobial susceptibility testing, January 2015) and tazobactam.

The MIC value was determined using the Citrobacter freundii ), Enterobacter aerogenes , Enterobacter cloacae ), Escherichia were determined for a combination of 19 isolates of Enterobacteriaceae species bacteria, including E. coli , Klebsiella pneumoniae , or Klebsiella oxytoca . The isolate was selected to represent the major species of Enterobacteriaceae (Lancet 2015; 385: 1949-1956) encountered in urinary tract infections and was tested for the presence of individual and multiple [beta] -lactamases (Including Clinical Infect Dis 2013; 56: 641-648), which comprises Class A ESBLs and Ambler Class C [beta] -lactamase. The activity on the isolate in this panel is expected to reflect the activity on clinical isolates of the same and / or other Enterobacteriaceae species producing the same or similar [beta] -lactamase. The results of these studies are shown in Table 2a-b.

Table 2a. The magnified-spectrum < RTI ID = Lactamase  Modern clinical < RTI ID = 0.0 > Enterobacteriaceae Separated  For the panel, Lactamase  MIC values measured on cephalosporin with and without inhibitor

Table 2b. Modern clinical enterobacteriaceae known to express magnified-spectrum [beta] -lactamase The MIC values measured for the combination of penicillin + beta-lactamase inhibitor available for the panel of isolates and the beta -lactamase inhibitor alone

The MIC of cechicosteride, cephofoxin and ceftibuten for ESBL-producing enterobacteriaceis tested in Table 2a-b was calculated using the CLSI / EUCAST (CLSI: ; EUCAST: European Antimicrobial Susceptibility Testing Committee) exceeds the MIC breakpoint. Therefore, Cechicem, Cephofoxin and Ceftybutene are not expected to be effective against modern ESBL-producing enterobacteriaceae. As shown in Table 2b, the combination of a? -Lactamase inhibitor (eg, amoxicillin + clavulanate or piperacillin + tazobactam) and a β-lactam (eg, penicillin) does not produce ESBLs Is active against enterobacteriaceae (e. G., AECO001) and ESBL-producing enterobacteriaceae (e. G., AECO1159) are generally resistant to combination. Thus, the addition of only a beta-lactamase inhibitor can not necessarily restore the activity of any beta -lactam drug against ESBL-producing enterobacteriaceae.

As shown in Table 2a, many of the ESBL-producing isolates were found to contain other orally-bioavailable third-generation cephalosporins (cefixime or cephalosporin) or cephapine (fourth generation veins used as comparators in this assay Lt; RTI ID = 0.0 &gt; cefotriene < / RTI &gt; alone. For example, ceftibuten has an MIC &lt; 8 μg / mL for 10 out of 19 ESBL-producing isolates. However, ceftazidime or the depth of sapphic did not have an MIC <8 μg / mL for ESBL-producing isolates in the panel. Cefepime also failed to reach cephebutene and achieved an MIC of <8 μg / mL for only 4 of the 19 ESBL-producing isolates. Significantly, the results show that ceftutaine has been shown to inhibit the deterioration by modern CTX-M-14 (e.g., AEAE1027, AECO1172) and CTX-M15 (e.g., AEAE1029, AKOX1009) Uniquely and unexpectedly more tolerant. CTX-M-14 and CTX-M15 expression isolates account for the majority of ESBL-producing isolates in the United States (Clin Infect Dis 2013; 56: 641-648). Despite the relative advantages of ceftibuten in comparison to other drugs of the same kind without beta -lactamase inhibitors, the majority of the ESBL-producing isolates described herein are susceptible to ceftibuten alone It was not.

As shown in Table 2a, the addition of clavulanate to ceftivuten was effective in isolates having relatively high MICs for each agent alone. This was an unexpected result when a recent survey of potentially useful old antibiotics by international experts concluded that ceftibuten did not have the potential for resistant bacteria (Clin Infect Dis 2012; 54: 268-274). Specifically, the addition of ceftibuten clavulanate decreased the concentration of cefuroxime from 16 / / mL to 2 / / mL against sheetrover fastidia ACFR1035, from 8 / / mL to 0.5 / / mL against enterobacter aerosin AEAE1029, (CTX-M-15 and TEM producer) at a concentration of 4 / / mL to 1 / / mL against E. coli AECO1147 (CTX-M-15 producer) ML to 0.25 [mu] g / mL for Klebsiella oxytoca AKOX1009 (CTX-M-15 producer), 16 [mu] g / mL to 1 [ Ella Nymonia (CTX-M-14 and SHV-12 producers) from 32 / / mL to 0.5 / / mL for AKPN1162 (CTX-M-15 and SHV- mL to 0.25 ㎍ / mL. Similar results have been observed in combination with tazobactam, but tazobactam has no known oral formulation and is therefore limited in therapeutic applications.

The effect of the combination of clavulanate and ceftibutene appeared in isolates with both relatively high and low MICs for ceftivuten alone. For example, AKPN1162 is relatively resistant to ceftivuten alone and showed a 64-fold reduction in MIC when clavulanate was added to cefotibuten (MIC decreased from 32 to 0.5 g / mL). Likewise, AKPN1159 was more sensitive than 8-fold to cefotubutin alone, whereas ceftivuten plus clavulanate showed a 64-fold reduction in MIC (MIC decreased from 4 to 0.063 g / mL or less) . The observed effect over the MIC range was an unexpected discovery with regard to the addition of clavulanate to ceftibuten, and the addition of cefixime + clavulanate (5 out of 19 isolates tested) or cephofoxin (19 Of the ESBL-producing isolate with MIC < 1 / / mL for the combination of ceftibuten + clavulanate (9 out of 19 isolates tested) compared to one . The persistence of the increased efficacy between cefthybutene and clavulanate at the lower end of the MIC range is due to the fact that ceftivuten has the ability to achieve PK / PD goals of 40% f T > MIC, as described in Example 5 below It is important for petit butene.

Other isolates tested (Citrobacter prundi ACFR1034, Enterobacter cloaca AECL 1065 and Enterobacter cloaca AECL 1067) were tested for their ability to inhibit the binding of any one of the three oral-bioavailable third-generation cephalosporins to the combination of clabulanate . These species, however, are often known to hydrolyze certain cephalosporins, and the chromosomal AmpC? -Lactamase (Scand J Infect Dis Suppl. 1986; 49: 38-45), which has an activity that clavulanate can not detect, Lt; / RTI &gt; Despite the differentially greater activity of ceftivuten as described above for the ESBL-producing isolate, the AmpC-expression segregate was found to be equivalent to ceftibuten, cefixime and cephalosporin regardless of the addition of clavulanate And high MICs. This is due to the undefined nature of the activity of ceftibuten in the ESBL-producing enterobacteriaceae (especially the CTX-M-15 and CTX-M-14 producers) and the broad applicability across all enterobacteriaceae or all beta-lactamases The effect of ceftibuten and clavulanate on these isolates, which can not be emphasized.

B. Cephalosporin and  β- Lactamase  Expanded combination of inhibitors MIC  evaluation

Based on the initial in vitro evaluation of cephalosporin and beta-lactamase inhibitor combinations, the MIC is based on an expanded panel of the combination of? -Lactamase inhibitor clavulanate and cephalosporin against thirteen enterobacteriaceae isolates Respectively. As mentioned above, cephalosporin and clavulanate were tested in a fixed 2: 1 ratio according to the method used for the amoxicillin and clavulanate tests. The tested cephalosporins were tested for their ability to inhibit cell proliferation in the presence of three different concentrations of Sephroxim (CFU), Sepharac (CFC), Cephprozil (CPR), Cepharaxine (CFL), LaRaCabe (LCB), Cefditoren CPD), cefdinir (CFD), cetearmium (CFX) and cetethibuten (CTB). The results are shown in Table 3. The combination of ceftivuten and clavulanate consistently showed the lowest MIC among the ten cephalosporins tested. For comparison, MICs for amoxicillin-clavulanate and ciprofloxacin were also measured.

Table 3. Cephalosporin  + Clavulanate  Of the expanded panel MIC  value

CFD: Cefdinir, CFD: Cefixir, CFD: Cefdinir, CFD: Cefdinir, CFD: Cefdinir, CFD: Cefixir, , CTB: Cettig Butene

Example  3: Extended-spectrum beta- Lactamase  ( ESBL ) Enterobacteriaceae  About Cettibuten and Clavulanate  Evaluation of the bactericidal activity of the combination

A. Minimum sterilization concentration

The bactericidal activity of ceftibuten-clavulanate on extended-spectrum beta-lactamase (ESBL) enterobacteriaceae was determined by isolating nine bacterial isolates expressing ESBLs from CTX-M and SHV (6 E. coli, 2 Klebsiella nymonae and 1 Enterobacter aerogenes) were measured and evaluated.

In order to measure MBC, log-phase bacterial cultures were incubated with a series of antibiotics according to the CLSI guidelines for the determination of the minimum inhibitory concentration (MIC) by the broth microdilution method &Lt; / RTI &gt; diluent. (CLSI Document M07-A9, Vol.32, No. 2. January 2012). Ceteth Butene: The clavulanate mass ratio was 2: 1 over a series of dilutions. Samples taken from wells without antibiotics in the assay plate at the beginning of the experiment were serially diluted in sterile physiological saline and spread on agar plates to determine inoculum cell density. After 18-20 h of incubation at 35 ° C in atmospheric air, the MIC values were recorded. Plates were shaken in a microtiter plate shaker for 1 minute and then returned to the incubator. After a total of 24 hours of incubation, the plates were shaken again for 1 minute. 10 mu L of sample was taken from the well at MIC and higher antibiotic concentration, diluted with 100 mu L of liquid medium on the surface of the agar plate, and spread across the plate. After incubation at 35 ° C overnight, the number of colonies was counted to determine MBC, defined as the minimum concentration of antibiotics that decreased viable cell density by more than 3 log ₁₀ compared to the cell density of the untreated control group at the beginning of the experiment.

Table 4 lists the ESBLs produced by each strain (beta-lactamase genotype) and the bacterial strains analyzed, including the antibiotic resistance of each strain. Table 4 also shows the MIC and MBC values obtained from this experiment. For eight out of nine strains, the MBC at 24 h was identical to the MIC (= MIC). For one strain, the MBC at 24 hours was twice as high as the MIC. If the MBC is not more than four times the MIC, the agonist is considered to be the most fungicide. (J Antimicrob Chemother (2006) 58 (6): 1107-1117). These results are consistent with the results that ceftibuten-clavulanate is a fungicide (3 log ₁₀ reduction in viable cell density) against ESBL E. coli, Klebsiella nymonia, and Enterobacter aerogenes.

Table 4. ESBL Enterobacteriaceae  about Cettig Butene - Clavulanate  Minimum sterilization concentration

AEAE = Enterobacter aerogenes; AECO = Escherichia coli; AKPN = Klebsiella pneumoniae; AMK = amitacine; AMP = ampicillin; ATM = aztreonam; CAZ = ceftazidime; CPT = ceftaroline; CTR = ceftriaxone; CTX = cytotoxicity; FEP = cephalim; GEN = gentamicin; LVX = levofloxacin; MBC = minimum sterilization concentration; MIC = minimum inhibitory concentration; OSBL = native-spectrum beta-lactamase; PTZ = piperacillin-tazobactam; TOB = tobramycin.

B. Cettig Butene - Clavulanate  Death kinetics

The kinetics of ceftibuten-clavulanate was measured on six bacterial isolates expressing CTX-M and SHV ESBLs (4 E. coli and 2 Klebsiella lupneumonia). Exponentially growing bacteria cultures were mixed with antibiotics in glass culture tubes and incubated with shaking at 37 ° C. The viability of the culture over time was monitored by serially diluting the sample in sterile physiological saline and spreading the diluted sample onto an agar plate. For cultures treated with the ceftibuten-clavulanate combination, the mass ratio was 2: 1 over a series of dilutions. For cultures treated with ceftibutene alone, the concentration was four times higher than the MIC of the ceftibuten-clavulanate combination. Meropenem was included as an 8-fold higher comparator than its MIC.

Table 5a shows the ESBLs produced by each strain (beta-lactamase genotype) and the analyzed, including the MIC of ceftibuten-clavulanate, ceftibuten and meropenem for isolates in time-kill experiments Bacterial strains are presented. For each bacterial strain, viable cell densities of representative cultures monitored in time-kill experiments are listed in Table 5b and graphically represented in Figures 1A-1F.

Table 5a: Analyzed in time-kill experiments Separation  About Cettig Butene - Clavulanay However, Cettig Butene  And Meropenem MICs

AECO = Escherichia coli; AKPN = Klebsiella pneumoniae; MIC = minimum inhibitory concentration; OSBL = native-spectrum beta-lactamase.

Table 5b: Cettig Butene - Clavulanate , Cettig Butene , or Meropenem  Treated ESBL  E. coli and Klebsiela Pneumoniae  Changes in Viable Cell Counts over Time

Abx = antibiotic; AECO = Escherichia coli; AKPN = Klebsiella pneumoniae; CFU = colony forming unit; CLA = clavulanate; CTB = cefthi butene; h = time; MIC = minimum inhibitory concentration; MEM = meropenem; OSBL = native-spectrum beta-lactamase.

The bold designation indicates a reduction of 3 log ₁₀ or more in viable cell density.

^The concentration of ¹ -week-old petit-butenes is equal to four times the concentration of MICs in the combination of cetethibuten-clavulanate.

Ceftibuten-clavulanate showed a time-dependent kill for all strains tested. Increasing the antibiotic concentration (up to 8 times the MIC) has little effect on kinetics. Bactericidality, defined as ≥3 log ₁₀ reduction in viable cell density, was achieved at 6 hours for all four of six strains at all ceftibuten-clavulanate concentrations. The remaining two strains achieved a 2 log ₁₀ reduction in viable cells at 6 hours, and a 3 log ₁₀ reduction at 24 hours, for all ceftibuten-clavulanate concentrations. The killing rate of ceftibuten-clavulanate, which is 8 times higher than that of each MIC, is slower than that of meropenem, achieving ≥3 log ₁₀ in viable cells from 2 hours to 4 hours.

Ceftibuten-clavulanate achieved more complete killing of ESBL-producing E. coli compared to ESBL-producing Klebsiella annuumonia. In the case of E. coli, 23 out of 24 cultures treated with ceftibuten-clavulanate two to eight times higher than the MIC had viable cell counts below or below the detection limit after 24 hours of culture. Of the eight cultures treated with ceftibuten-clavulanate, only two were at or near the detection limit at 24 hours for Klebsiella pneumoniae.

Regrowth was only observed in 24 ESBL-producing E. coli cultures treated with ceftibuten-clavulanate two to eight times higher than MIC. A single example of E. coli regrowth was observed in cultures of AECO1156 treated with 8 times the MIC of ceftibuten-clavulanate (data not shown) and not reproducible. Regrowth was observed in one of the eight Klebsiella pneumoniae cultures treated with ceftibuten-clavulanate. This re-growth occurred in cultures of AKPN1159 treated with twice the MIC of cetethubuten-clavulanate and did not occur again in duplicate experiments.

In summary, the combination of ceftibuten-clavulanate showed a time-dependent death to ESBL-producing E. coli and Klebsiella pneumoniae. All tested ceftibuten-clavulanate concentrations (2 to 8 times higher than MIC) showed bactericidal efficacy within 6 hours for 4 out of 6 strains (3 E. coli and 1 Klebsiella annuumonia). For the remaining strains (1 E. coli and 1 Klebsiella annuumonia), ceftibuten-clavulanate showed bactericidal activity within 24 hours. Regrowth of cultures treated with ceftibuten-clavulanate was scarcely observed (1 out of 24 Escherichia coli and 1 out of 8 colonies).

Example  4: Gram-negative for pathogen Cettig Butene  And Clavulanate MIC ₉₀ Measurement of

A. Enterobacteriaceae Separator

The antimicrobial activity of ceftibuten-clavulanate, ceftibuten alone or clavulanate alone exhibited an isolate exhibiting an extended spectrum beta-lactamase (ESBL) -type, collected in the US and Europe during 2014-2015 &Lt; / RTI &gt; total 385 E. coli and 126 Klebsiella pneumoniae. To evaluate the ESBL-phenotype, 511 isolates were cloned into CTX-M groups 1, 2, 8 + 25 and 9, TEM wild type (WT) and ESBL, SHV WT and ESBL, ACC, ACT / MIR, CMY-2-, DHA, FOX, KPC And a microarray-based assay (Check-MDR CT 101 Kit; Checkpoints, Netherlands) targeting genes encoding NDM-1 and the like were tested for the presence of? -Lactamase. The most common amino acid changes that extend the spectrum of TEM and SHV enzymes are detected by this assay and include E104K, R164S / H or G238S for TEM and G238A / S and E240K for SHV. These organisms were collected from urinary tract infections (430 isolates) or from bloodstream infections (81 isolates) with the cause of urinary tract infections.

Table 6a summarizes the results of β-lactamase screening for the 511 Enterobacteriaceae strain selected for this study. Although the 240 isolates tested were positive for only one detected beta-lactamase encoding gene, all other isolates carried several beta-lactamases.

Table 6a. Separation  Results of molecular screening

MIC values, including MIC ₅₀ and MIC ₉₀ values, were determined for all isolates under the following conditions: ceftivuten alone (range 0.015 to 32 ug / mL); Ceftibuten-clavulanate (2: 1 ratio, 0.015 / 0.008 to 32/16 g / mL); Ceftibuten-clavulanate with clavulanate fixed at 2 ug / mL; 0.015 / 2 to 32/2 / / mL); Ceftibuten-clavulanate with clavulanate fixed at 4 ug / mL; 0.015 / 4 to 32/4 쨉 g / mL) and amoxicillin-clavulanate (cetibutene-clavulanate with clavulanate fixed at a ratio of 2: 1, 0.015 / 0.008 to 32/16; 0.015 / To 32/2 &lt; / RTI &gt; The MIC values were measured using a reference frozen culture medium microdilution panel containing Mueller-Hinton medium, cationically adjusted according to CLSI (CLSI, M07-A10) (CLSI.) . (CLSI. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically ; Approved standard-tenth edition. Clinical and Laboratory Standards Institute, Wayne, PA, 2015). Other antimicrobial agents were also evaluated for comparison. Quality control (QC) strains that have been incidentally tested in clinical isolates and inoculum density assays are monitored by colony numbers. QC scope and interpretation criteria CLSI (M100-S26) antimicrobial susceptibility testing (AST) guidelines (CLSI Performance standards for antimicrobial susceptibility testing ;... 26th informational supplement CLSI document M100-S25 Clinical and Laboratory Standards Institute, Wayne, PA, 2016 ). The tested QC strains were E. coli ATCC 25922 and ATCC 35218, Klebsiella pneumonia ATCC 700603, and Pseudomonas aeruginosa ATCC 27853. The QC results for comparative agonists were within the published range of CLSI (M100-S26).

The activity of ceftibuten ± clavulanate is summarized in Table 6b for a total collection of the 511 enterobacteretheia isolate. The activity of ceftibuten ± clavulanate compared with other antimicrobial agents is shown in Table 6c. Table 6c, MICs are CLSI (M100-S26, 2016) and EUCAST 2016 (EUCAST:. European Committee on Antimicrobial Susceptibility Testing breakpoint tables for interpretation of MICs and zone diameters Version 6.0, 2016) was used to analyze all of the instructions immunity ( R), intermediate (I) or susceptible (S).

a. The criteria published by CLSI [2016] and the European Antimicrobial Susceptibility Testing Committee (EUCAST) [2016]

b. Sensitivity - Intermediate interpreted as dose dependent

As shown in Table 6b and 6c, three Petit-butene alone _{(MIC 50/90, 8 /} > 32 ㎍ / mL) is exhibited limited activity on the collected water separation 511 Enterobacter bacteria seae, elevated MIC values are collected Lt; RTI ID = 0.0 &gt; cephalosporin &lt; / RTI &gt; and / or aztreonam. Ceftic buten inhibited only 56.0% and 18.6% of the isolates applying CLSI and EUCAST breakpoints, respectively. In contrast, the ceftibuten-clavulanate combination showed a MIC ₅₀ value 16 to 32 times lower compared to ceftibuten alone for all 511 isolates. Cetylbutene-clavulanate inhibited 76.5 and 81.4% of the isolate at ≤1 and ≤8 ㎍ / mL, when tested with fixed 2 ug / mL clavulanate, at a fixed concentration of 4 ug / mL When clavulanate was tested, 76.5 and 82.4% of the isolate was inhibited at the same concentration. When ceftibuten-clavulanate was tested at a 2: 1 ratio, 73.8 and 82.0% of the isolate were found to be ≤ 1 and ≤ 8 ㎍ / mL (CLSI and EUCAST breakpoints of ceftibuten used for comparative purposes) .

Three Petit butene-activity of clavulanate combination KPC (25 isolates; for all inhibitor concentration _{MIC 50/90 = 8/32 ㎍ /} mL) and transferable AmpC (57 isolates, with respect to all the inhibitor concentration MIC _{50 / 90} = > = 32 / &gt; 32 [mu] g / mL).

The ceftibuten-clavulanate combination was highly active against the 365 isolate producing the CTX-M enzyme (the most common beta-lactamase gene detected in the tested isolate). This set excluded isolates carrying genes encoding transposable AmpC and / or carbapenemase. MIC _50/90 value is a fixed 2 ㎍ / mL, frozen 4 ㎍ / mL and 2 were respectively 0.25 / 0.5, 0.25 / 0.5 and 0.5 / 1 ㎍ / mL with respect to 1 ratio, the combination thereof is ≤ 1 ㎍ / mL inhibited from 92.9 to 96.2% of the isolate and from 97.5 to 97.8% of the isolate at &amp;le; 8 mu g / mL. Three Petit-butene alone _{(MIC 50/90, 8 /} > 32 ㎍ / mL) inhibited the activity is limited ≤ 1 ㎍ / mL in water, separating only 19.7%, ≤ 8 ㎍ / mL 64.4% of water separated from the. The ceftibuten-clavulanate combination also inhibited all 18 isolates carrying SHV ESBL enzyme (without carbapenemase and transposable AmpC) at ≤ 0.5 ㎍ / mL, regardless of the concentration of inhibitor. Overall, the ceftibuten-clavulanate combination (MIC ₅₀ and MIC ₉₀ range, 0.25-0.5 and 0.5-1 ug / mL) had an ESBL enzyme identified and a total of 387 without carbapenemase or transposable AmpC enzyme Lt; / RTI &gt;

For each 379 Escherichia coli or Klebsiella pneumoniae isolate genotyped for CTX-M, TEM or SHV ESBLS, MICs were used to treat cefotubentin alone or ceftibuten + clavulanate in a 2: Respectively. The percentage of these isolates inhibited in each MIC is shown in Fig. The MIC ₉₀ for ceftibuten: clavulanate, ceftibutene, and amoxicillin: clavulanate are about 1, 32, and 16 ug / mL, respectively.

The 23 isolates showing negative results for the screened beta -lactamase gene showed an MIC value of at least &lt; RTI ID = 0.0 &gt; 8 &lt; / RTI &gt; g / mL for at least one of the ceftivuten plus clavulanate combinations. All these isolates were E. coli from 21 hospitals located in six countries. Preliminary data from whole genome sequencing of these isolates indicated the presence of the inducible chromosome AmpC.

Overall, the presence of the tested clavulanate at a fixed 2 or 4 [mu] g / mL or 2: 1 ratio reduced the Cetitbutene MIC value for the UTIs related UTIs or the enterobacteriaceae isolates collected from the blood stream . This effect appeared regardless of geographical area or bacterial species. The ceftut-butene-clavulanate combination exhibited very good activity on isolates producing ESBLs (CTX-M and SHV ESBL enzymes) and the activity of these combinations of beta-lactam / inhibitor was significantly higher when compared to ceftibuten alone At least 16-fold higher. Cetitbutene with or without clavulanate showed limited activity against isolates carrying genes encoding carbapenemase and / or transposable AmpC.

B. A / B Gram-negative organism biological threat biothreat ) Pathogenic MIC  evaluation

In vitro efficacy of ceftibuten and ceftibuten-clavulanate (2: 1 ratio) on model strains of A / B gram-negative biologic threat pathogens in four categories was assessed using standard MIC assay protocols. The strain was identified as Yersinia pestis) Colorado92, yato pathogen (Francisella tularensis ) ShuS4, Burkholderia mallei China7 and Burkholderia pseudomallei ) 1026b. The measured MICs for both ceftibuten and ceftibuten-clavulanate were 0.03, 0.25, 1-2, and 8 ug / mL, respectively. The discovery that the MICs of ceftutin and combinations are substantially the same may be due to the fact that these strains do not carry the ESBL enzyme.

Example  5: MIC  And Pharmacokinetics  Based Cephalosporin  Determine the feasibility of administration

To determine the feasibility for oral administration, MIC data were analyzed in terms of the pharmacokinetic properties of cephalosporin. Pharmacokinetic and pharmacokinetic (PK / PD) index is a free drug in human plasma concentrations that exceed the MIC for 40% of the dosing interval (Clin Infect Dis 1998; 26: 1-10), generally 40% f T > MIC.

The PK / PD index and target size associated with the efficacy of cephalosporin against Enterobacteriaceae are well described in the literature for certain cephalosporins (see, e. G., Table 7). Existing data indicate that ceftytrene has, among other things, less than optimal pharmacokinetic properties, particularly in the class, such as: lower bioavailability (for ceftibuten, (14% for Spectracef® Package Insert, Purdue Pharmaceutical Products, Stamford, CT: 2005), a lower maximum concentration (Cmax), a relatively shorter half- See Table 7, Package Insert References and Pharmacotherapy 1997; 17: 707-720). The MIC ₉₀ for ceftitholene was reported to be 0.5 μg / mL in several serotypes of enterobacteriaceae isolates that did not produce ESBLs (ESBL-) (BMC Infect Dis 2012; 12: 228 and Diagn Microbiol Infect Dis 2010; 67 : 251-260). Pharmacokinetic data for cefditoren show that the maximum free drug concentration does not exceed 0.3 μg / mL with nearly approved dosing (Table 7) and the half-life is less than 2 hours. Therefore, even though more doses of cefditoren are given more frequently, with ESBL inhibitors (Rev Esp Quimioter 2007; 20: 51-60), even with MICs ranging from 0.12-2 ug / mL to ESBL + isolates and Joseph Ditto alkylene It will not be easy to achieve a systemic exposure of more than 40% f T> MIC against Enterobacter bacteria produce ESBL- seae.

Table 7. 3rd Generation Oral - Bioavailable Cephalosporin  About Pharmacokinetics  parameter

Cmax: maximum total drug concentration in plasma; f Cmax: Free / non-binding maximum drug concentration in plasma | ¹ Cedax® Package Insert. Shionogi USA, Florham Park, NJ: 2009. ² Vantin® Package Insert. Pharmacia and Upjohn Company, New York, NY: 2013. ³ Suprax® Package Insert. Lupin, Baltimore, MD: 2016. ⁴ Spectracef® Package Insert. Purdue Pharmaceutical Products, Stamford, CT: 2005. a line from the old The highest plasma concentration; ^b may vary up to 9 hours for some normal applicants.

40% f T> is not known whether or not possible to achieve for the β- lock Tama inhibitor in combination with any of the other as a modern cephalosporin to ESBL- generated Enterobacter bacteria seae for PK / PD MIC of the target presence. Furthermore, it has not previously been known whether any of the cephalosporins exhibit excellent activity for use in combination with modern ESBL-producing enterobacteriacease inhibitors or? -Lactamase inhibitors.

Example 2 demonstrates that the combination of ceftibuten and clavulanate tested in a 2: 1 ratio can achieve MICs of ≤ 2 ug / mL for a representative panel of enterobacteriaceae producing modern ESBLs .

In contrast, the combination of CeCNic + clavulanate achieved MIC = 4 [mu] g / mL for at least one non-AmpC expression isolate in the panel, and Cephofocus + Clavulanate achieved four non-AmpC MIC = 4 [mu] g / mL for expression isolates. Thus, when combined with clavulanate, it is necessary to achieve sepik shim 40% f T> 2 or 4 ㎍ / mL, Joseph Four doksim it is necessary to achieve a 40% f T> 4 ㎍ / mL. To assess whether PK / PD goals are feasible, the MIC data were evaluated in terms of the pharmacokinetic properties of the cephalophosphorins presented in Table 7.

The free maximal concentration ( f Cmax) after a single 400 mg oral dose of Cepheid is 1.3 [mu] g / mL, confirming and maintaining plasma concentrations of higher doses of &lt; RTI ID = 0.0 > . This is very challenging to achieve at achievable doses, considering that the dose of &lt; RTI ID = 0.0 > 400 mg &lt; / RTI &gt; is associated with a non-proportional increase in Cmax (Pediatr Infect Dis J 1987; 6: 963-970). Oral administration of 2 g Septic can achieve a f Cmax of only 2.7 ug / mL, and even if administered three times a day, MIC would not be easy to achieve 40% f T> MIC. In addition, these known pharmacokinetic data indicate that it would be possible to achieve f Cmax &gt; 4 [mu] g / mL with a feasible oral dose of cephex.

If ceftazidime is administered orally to a dose of 400 mg (Vantin® Package Insert Pharmacia and Upjohn Company, New York, NY: 2013) at doses exceeding the approved regimen for 100 mg of simple urinary tract infections every 12 hours, f . Cmax is about 3.1 ㎍ / mL, that is the target of 4 ㎍ / mL are expected than chef Four doksim the case where orally administered 800 mg, approximately 5.4 ㎍ / mL, but the f Cmax is achieved (J Antimicrob Chemother 1990; 26 : e21-e28), concentrations <. decreases to 4 ㎍ / mL this dose of 800 mg is 40% f T> in less than one half-life of (2.9 hours at this dose), at least a day in order to achieve the MIC 4 Day, i.e. a total daily dose of 2.4 g or more is not feasible.

In contrast, oral doses of 400 mg of ceftutilin achieve a free drug concentration of> 2 μg / mL for at least 6 hours after drug administration. (Adjusted from Cedax® Package Insert, Shionogi USA, Florham Park, NJ: 2009) and from Figure 3 (Lin et al. (1995) Antimicrobial Agents and Chemotherapy, 39: 359-361). This data supports a 40% fT > MIC of 2 μg / mL at two daily doses of ceftitbutene, or up to three times daily.

Table 8. Twelve healthy male volunteers Cohort  Single within 400 mg  The mean plasma concentration (total and free) of ceftibuten after administration was &lt; RTI ID = 0.0 &gt; ^One

¹ Cedax® Package Insert. Shionogi USA, Florham Park, NJ: 2009.

Importantly, although pharmacokinetic data for these cephalosporins were known (Table 7), without understanding clavulanate for modern ESBL-producing isolates and MICs of these cephalosporin combinations, It was not clear that this feasible treatment regimen was likely to achieve 40% fT > MIC.

Example  6: Clavulanate  + Cettig Butene After administration, β - Lactamase  Inhibitor effect measurement

The post-β-lactamase inhibitor effect (PBLIE) of the β-lactamase inhibitor clavulanate in combination with any of various β-lactams, ceftibuten or other cephalosporins Respectively. Certain [beta] -lactamase inhibitors are known to have an effect after administration of [beta] -lactamase inhibitor (PBLIE), and inhibitors continue to show efficacy even when they are no longer present. PBLIE can vary widely for different? -Lactams and? -Lactamases, and for different pathogen isolates expressing different types and amounts of? -Lactamase (Antimicrob Agents Chemother 1996; 40: 2796- 2801, J Antimicrob Chemother 2004; 53: 616-619, Antimicrob Agents Chemother 2014; 58: 2434-2437). PBLIE has been previously defined for beta-lactam inhibitors such as cephalosporin + sulbactam, tazobactam and avibactam (J Antimicrob Chemother 2004; 53: 616-619, Antimicrob Agents Chemother 2014; 58: 2434-2437 , Lett Appl Microbiol 2016: doi: 10.1111 / lam.12592), none reported PBLIE for cephalophosphorins, such as ceftibuten, in combination with clavulanate. Therefore, whether PBLIE against clavulanate is present when used in combination with ceftibuten for a contemporary common ESBL-producing isolate, such as Escherichia coli isolate expressing CTX-M-15 (AECO1078) Was not known.

A. CTX In E. coli expressing -M-15 With clavulanate  together Ceptibuten  PBLIE for

To evaluate the PBLIE, E. coli AECO1078 isolates (1 μg / mL) were incubated with 2 μg / mL ceftibutene (CTB) or 2 μg / mL ceftibuten (CTB) and 1 μg / mL clavulanate (CLA) Were cultured. After 1 hour, cells were washed and then diluted 1,000-fold with CTB alone, or with media containing CTB and CLA, without antibiotic (abx). The number of CFU / mL of samples spread on the agar plates was measured at one hour, including before and after at one hour.

The bactericidal activity under the tested conditions is shown in Figure 4A. The results confirm that in vitro MIC data of Example 2 confirms that the MIC of AECO1078 for ceftibuten alone is 32 占 퐂 / mL and the MIC for ceftibuten + clavulanate (2: 1) is 1 占 퐂 / mL , See Table 2a-b. Cetibutene alone had minimal effect on the in vitro growth of AECO1078 (Fig. 4A). The line with squares (pre-and post-wash) Cleaning). The combination of ceftutaine and clavulanate resulted in fast fungicidal activity (Fig. 4A). The line with diamonds (ceftibuten + clavulanate pre- and post-wash) And after-washing).

In addition, clavulanate exhibited a sustained PBLIE of 2.5 hours when used with ceftibuten in the modern CTX-M-15-producing Escherichia coli isolate (Fig. 4A) Compare petit butene + pre-clavulanate - after washing and after cettivutene alone - wash) and circled lines (pre- and post-wash without antibiotics). Not only was the regrowth delayed, but clavulanate was removed and bacterial killings persisted for approximately 1 hour after ceftivuten remained (Fig. 4A), with a downwardly directed triangular line (ceftibuten + clavulanate Compare 1 hour and 2 hour points on pre-wash and post-cettybutene alone-wash).

The PBLIE increased growth of 1 log ₁₀ for the cultures treated with the combination compared to the cultures exposed to beta-lactam only during both the treatment and recovery periods, and then the additional It is time. PBLIE is distinguished from post-antibiotic effect (PAE). PAE is an additional time required to increase 1 log ₁₀ growth compared to untreated control cultures for cultures treated with antibiotics. As shown in Figure 4A, the PBLIE is clearly distinct from the post-antibiotic effect (PAE; continuous inhibition of bacterial growth after discontinuation of antibiotic exposure) (Figure 4A, (Before clavulanate - after washing and after cettivutene alone - washing) and a line with an upwardly directed triangle (Cettibuten + clavulanate before - wash, after washing without antibiotic). The PAE is only about 0.10 hours (Fig. 4A), with a square line (before and after washing with Cettibactone alone) and a line with an upwardly directed triangle (Cettibuten + Clavulanate pre-wash, without antibiotics After washing). There was no persistent bacterial death after the removal of ceftibuten + clavulanate.

B. Various Cephalosporin  And Separation  About PBLIE

In order to determine whether the PBLIE shown in the combination of ceftibuten and clavulanate is applicable to other cephalosporins and other isolates, it is also possible to use cefixime + clavulanate, cefpodocin + clavulanate and ceftibuten + The PBLIE for the bulanate was prepared from E. coli expressing CTX-M-15 (AECO1078), Escherichia coli expressing CTX-M-15 and TEM-OBSL (AECO1157) and Klebsiella pneumoniae expressing SHV- AKPN1159). The PBLIE was analyzed as described above with a mass ratio of the cephalosporin: clavulanate constant at 2: 1 and the concentration of cephalosporin listed in Table 9.

Table 9: Other ESBL Separation  About Cephalosporin  + Clavulanate PBLIE  And PAE

AECO1078: CTX-M-15 Escherichia coli; AECO1157: CTX-M-15 + TEM-OBSL Escherichia coli; AKPN1159: SHV-12 Klebsiella pneumoniae

The periods of PBLIE and PAE for each condition are summarized in Table 9. For each strain tested, the clavulanate-induced PBLIE was the longest in cephebutene. The clavulanate-induced PBLIE was substantially shorter in the cetearmin, and the Cefpodocin did not exhibit measurable clavulanate-induced PBLIE.

In Example 2, a large difference in PBLIE is surprising since it exhibited a large decrease in MIC for most of the tested strains of Cechicine + clavulanate and Cefpodocin + Clavulanate (see Table 2a-b). In addition, CEchicine + clavulanate had the second lowest MICs (after Cefotubentin) among all the cephalosporins tested for almost all isolates (see Table 3). This demonstrates that PBLIE does not necessarily correlate with a large decrease in MIC when combining a beta-lactamase inhibitor with cephalosporin.

Representative PBLIE results for clavulanate in combination with alternative cephalosporin for E. coli expressing CTX-M-15 (AECO1078) are summarized in Figure 4B (septicem) and Figure 4C (ceftourate). As shown in Figure 4B, similar to the results described for clavulanate with cettivuten in the previous section, the combination of clavulanate and Cepheid resulted in fast fungicidal activity (see Figure 4B) Compare the clavulanate line with the line without antibiotics). However, unlike the ceftibuten-clavulanate combination, clavulanate did not exhibit persistent PBLIE when used with the cefixime for this CTX-M-15-producing E. coli isolate. Regrowth was delayed to a minimum and no reduction in CFU / mL was observed after the clavulanate was removed and remained in the replicas (Fig. 4B), showing the pre-washing, post-cefixime after- 1 hour and 2 hours are compared). Similarly, as shown in Figure 4C, the combination of cephofoxin and clavulanate did not have measurable PBLIE (Table 9, Figure 4C).

Representative PBLIE results for clavulanate in combination with alternative cephalosporins for E. coli isolates expressing CTX-M-15 and TEM-OBSL (AECO 1157) are shown in Figure 5A (clavulanate +/- ceftibuten) , Fig. 5B (clavulanate +/- cefixime) and Fig. 5C (clavulanate +/- cefpodocaine). As shown in Fig. 5A, despite the minimal effect of ceftibuten alone, ceftivuten alone after clavulanate continued to reduce the number of CFU / mL for at least 3 hours. The same ESBL-producing enterobacteriaceae cechicine + clavulanate (Fig. 5B) and cephalosporin + clavulanate (Fig. 5C) each had or were significantly shorter than PBLIE.

Representative PBLIE results for clavulanate in combination with alternative cephalosporin for Klebsiella pneumoniae (AKPN1159) expressing SHV-12 are shown in Figures 6A (clavulanate +/- ceftibuten), Figure 6B (Clavulanate +/- cefixime) and Figure 6C (clavulanate +/- cefpodocaine). As shown, the PBLIE effect observed after treatment of AKPN1159 showed an effect similar to that described above for the E. coli isolate tested.

C. Medication Therapy

This data supports the feasible administration of ceftibuten + clavulanate to effectively treat infection due to ESBL-producing enterobacteriaceae. As discussed in Example 5, pharmacokinetics of ceftibuten is likely to exceed PK / PD for efficacy at a feasible human dose given ceftivuten alone, two or three times a day, and bacterial Allow sufficient exposure of ceftitbutene throughout the dosing interval. However, the plasma half-life of clavulanate is shorter than the plasma half-life of cefoti-butene (approximately one hour to 2.4 hours) (Excerpta Medica, International Congress Series 544; 1980, pages 117-121. Cedax® Package Insert. Park, NJ: 2009). Therefore, although the pathogen is initially exposed to two compounds at high concentrations, the clavulanate concentration will decrease below the PK / PD threshold concentration (the desired amount) prior to cefotibuten. The combination of ceftibuten + clavulanate is more likely to demonstrate clinical efficacy if clavulanate can contribute to bacterial growth inhibition after its concentration drops below the target threshold, as shown in the PBLIE results. Such data may also be a factor in the justification for human dosing regimens.

The observed MICs of ceftibuten + clavulanate support the achievement of PK / PD targets for modern ESBL-producing enterobacteriaceae. Using data from MIC experiments and pharmacokinetic analyzes, the potential human dose range for ceftibuten and clavulanate in the final combination product was determined. The total daily dose of ceftibuten was determined to be in the range of 800 to 1800 mg (two to three divided doses), and the total daily dose of clavulanate was 250 to 750 mg (two to three divided doses And the ratio of ceteth butene: clavulanate was 1: 1 to 7: 1.

The MICs observed for cecicium + clavulanate and cefpodocin + clavulanate are based on the above described analysis of known systemic exposures achieved by these cephalosporins with respect to the PK / PD targets required for efficacy, / PD Do not support the goal.

Example  7: Cettig Butene  And Clavulanate Pharmacodynamics  And administration

A. Chemostat  Model( chemostat  model) MIC  Assessment of Excess Free Drug Concentration

One. Cettig Butene

A single compartment of the in vitro chemosultant infection model showed that the amount of time (expressed as a percentage of the dosing interval) over which the free drug concentration for ceftutin exceeds MIC (% f T> MIC) It was used to determine if there was a correlation. In addition, this model was also used to determine the magnitude of exposure of cefoti-butene associated with stagnation, 1-log, or 2-log reduction in bacterial growth.

a. Way

The 300 ml of the free chemomastat model was diluted in a cation-adjusted Mueller Hinton II Broth (CAMHB) (20-25 mg / L calcium, 10-12.5 mg / L magnesium; Becton, Dickinson and Company, Sparks, MD) and placed in a water bath at 35 ° C. During the experiment, a magnetic stirrer was used for continuous mixing of the contents. The chemostat model was inoculated with 10 ⁶ CFU / mL of bacteria.

Once inoculated, the bacteria enter the exponential growth phase for 30 minutes before exposure to antibiotics. For each drug exposure / bacterial combination, the experiment was conducted for 24 hours and consisted of a drug-free control and two experimental (i. E., Drug containing) replicate models. Data from two replicate models were treated as independent exposures when given some expected variability at concentrations obtained due to small discrepancies in volume flow between the chemostat models.

A peristaltic pump (Masterflex L / S model 7524-40; Cole-Parmer, Vernon Hills, IL) was set up to inject CAMHB into the model at the desired removal rate for the drug. Liquid broth samples were collected from the model throughout the experiment to determine free drug concentration and bacterial density. Always carryover is minimized by a series of dilutions of the sample. Bacterial density was calculated after incubation at 37 ° C for 18-24 hours. The low detection limit of bacterial density was 1.7 log ₁₀ CFU / ml. log ₁₀ CFU / mL plotted against time to establish a time-kill curve

For testing with ceftibutene alone, E. coli (ATCC 25922) was used. Exposures targeting 10, 20, 40, 60, 80 and 100% fT > MIC for 24 hours were calculated and administered to the chemostat model. The dosing was performed with a goal of 10 μg / mL ceftibuten max, designed to simulate the maximum clinically achievable ceftibuten concentration in humans. A control model was provided to define the 0% f T> MIC results. Bacterial density was assessed at 0, 1, 6, 12 and 24 hours. The drug concentration was evaluated at the peak and the lowest of each administered dose to achieve the desired exposure and at least one other midpoint concentration for each interval. This resulted in at least three usable ceftibuten concentrations at each dosing interval to calculate f T> MIC. A change in log ₁₀ CFU / ml at 24 hours was the primary endpoint of the exposure response relationship. Congestion, f T> MIC size in the 1-log, or a 2-log reduction was assessed after the matched data to the inhibitory S-shaped (sigmoidal) Emax model in Phoenix WinNonlin (Pharsight Corp. Mountain View, CA).

b. result

As shown in Figure 7A,% f T> MIC is associated with a CFU reduction,% f T> MIC was confirmed that there may be a PD driver (driver) with respect to the three Petit butene. Congestion, f T> showed a MIC are shown in Table 10, which is approximately 50% to 60% f T> MIC is the final bacterial congestion for 1-log kill effect to achieve 1-log, or a 2-log CFU reduction . This result is consistent with the data for antibiotics of the cephalosporin family, with% f T> MIC being associated with stagnation and 40% f T> MIC being associated with stasis and 60% to 70% being associated with maximal bacterial death, (Craig WA, Clin . Infect. Dis . (1998) 26: 1-10).

Table 10: CFU  Associated with reduction Ceptibuten  About f T > MIC  exposure

2. Cettig Butene  + Clavulanate

a. Way

Using the in vitro chemostat model described above, a dose-classification study of clavulanate was conducted to determine the effect of ceftibuten exposure to 50% to 60% fT > MIC for CTX-M-55-producing E. coli strains Lt; / RTI > This isolate had cetethbutene MIC> 64 μg / mL, clavulanate MIC> 32 μg / mL, and ceftibuten + clavulanate MIC 1 μg / mL. The in vitro model injection rate achieved a ceftutin exposure of about 60% f T> MIC at 1 μg / mL of MIC administered every 8 hours with each ceftutuben dose being 10 μg / mL with ceftibuten maxima . Clavulanate remained in 24 hours, 12 hours, or every six hours free maximum concentration (Cmax f), curved under the free area (f AUC _{0 -24),} and the free concentration of the threshold excess (% f T> threshold) exposure Is added to the model to achieve a percentage of the time.

The ceftibuten alone test was provided with zero exposure of clavulanate. Bacterial densities were collected at 0, 1, 6, 12, 18, and 24 hours for each experiment, and concentrations of both ceftibuten and clavulanate were identified at three or more sampling points during each interval. For each freezer used for PK sample collection, 30 μl of tazobactam was prefilled to prevent degradation after collection of ceftitbutene. The exact volume of 300 [mu] l of analyte (cefthybutene and clavulanate) containing liquid medium was obtained from the Kemostat model and mixed with ostrich bactam before freezing at -80 [deg.] C. Changes in log ₁₀ CFU / ml at 24 hours were plotted for PD exposure and analyzed using the inhibitory S-shaped Emax model of Phoenix WinNonlin. The following PD exposure relationships were evaluated: f Cmax, f AUC _{0 -24} , f Cmax / Threshold, f AUC _{0 -24} / Threshold, and% f T> Threshold, It is the same as Cettibuten + clavulanate MIC. Final PD indices were selected based on R ² , AIC, and visual inspection of the plot.

Once the PD index for clavulanate is measured, the various clavulanate exposures are combined with fixed cefotubentin exposures, and ~ 1 for ceftibuten + clavulanate MIC of 4 beta-lactamase producing enterobacteriaceae -log CFU reduction (ESBL phenotype shown in Table 11). Cefotubutin alone was provided with zero exposure to clavulanate. The maximum value of cefthi-butenes was aimed at 10 ㎍ / ml. Bacterial densities were collected at 0, 1, 6, 12, 18, and 24 hours for each experiment, and concentrations of both ceftibuten and clavulanate were identified at three or more sampling points during each interval. For each freezer used for PK sample collection, 30 μl of tazobactam was prefilled to prevent degradation after collection of ceftitbutene. The exact volume of 300 [mu] l of analyte (cefthybutene and clavulanate) containing liquid medium was obtained from the Kemostat model and mixed with ostrich bactam before freezing at -80 [deg.] C.

Changes in log ₁₀ CFU / ml at 24 hours were plotted for PD exposure and analyzed using the inhibitory S-shaped Emax model of Phoenix WinNonlin. For each of the isolates, the exposures that resulted in stagnation, 1-log, and 2-log CFU reduction were calculated. The threshold varied from 1-2% diluted above and below the ceftivutene + clavulanate MIC of each of the isolates. Final PD indices were selected based on R ² , AIC, and visual inspection of the plot.

b. result

As shown in FIG. 7B and Table 11, approximately 30% to 40% of clavulanate f T> C _T for C _T of 0.25 to 1 μg / mL was used in combination with ceftibutene to achieve final bacterial stagnation . Additionally, the results support that the amount of time over which the free drug concentration exceeds the critical concentration ( f T > CT) is a factor associated with PD for clavulanate (FIG. 7B).

In line with the results for PBLIE ESBL- generated Enterobacter bacteria seae, clavulanate exposure period (30% to 40% f T> CT) is full of the three Petit butene exposure in order to provide protection against β- lock Tama Kinase (50% f T > MIC).

Table 11: Clavulanate  The stagnation due to the threshold and 1-log CFU  Reduced exposure requirements Between the separated water  Comparison summary Pharmacodynamics  compatibility

Note: CTB = Ceptibuten, CLAV = clavulanate, N / A = data not available. MIC = minimum inhibitory concentration, ESBL = extended spectrum beta-lactamase

B. Cettibuten and On clavulanate  About Pharmacokinetics modelling

PK models for ceftibuten and clavulanate were constructed by digitizing existing PK data from literature provided as a set of modeling data. One compartment PK model with first order elimination of cetethbutene and two compartment PK models with first order elimination of clavulanate have been developed. The relationship between the clearance (CL) and the creatinine clearance (CLcr) was measured for both ceftibuten and clavulanate and was applied as a continuous covariate in each PK model. Monte Carlo simulations were performed using a uniform distribution over CLcr from 85 to 145 mL / min in a patient with normal renal function with a range of dosing regimens (cefotitanone in combination with clavulanate 125 or 187.5 mg TID 300 or 400 mg TID) (i. E., Ceftibuten exposure to a critical concentration of 0.25 to 1 g / mL was 50% f T> MIC, and clavulanate exposure is 30% to 40% fT > CT). 1000 simulations were performed and the likelihood of achieving the goals was evaluated for each scenario.

Using a PK / PD target for cephalosporin and clavitanate and ceftibuten PK data, an exemplary human dose that is likely to be effective against an enterobacteriacease with MIC ≤ 2 ug / mL for cefotibuten Respectively. The analysis showed that ceftivuten exhibited ceftivuten as an example total daily dose given as 375 to 562.5 mg, e.g., 125-187.5 mg TID, clavulanate (e.g., from cleavage by the target beta-lactamase, , This efficacy goal can be achieved at an exemplary total daily dose given as 900 to 1200 mg, for example 300-400 mg TID. The results of this study demonstrated that there are various target scenarios where the probability of achieving targets (PTA) in excess of 90% was achieved.

Table 12: Cettig Butene  ( 400 mg , TID ) Clavulanic acid  ( 125 mg , TID ) And normal renal function ( CrCL :> 80 mL / Min), the free drug concentration With MIC  C _T Percentage of cases exceeding.

Ceft = ceftibutene; Clav = clavulanic acid; CrCL = creatinine clearance; MIC = minimum inhibitory concentration C _T = critical concentration; TID = 3 times a day.

Table 13: Cettig Butene  ( 400 mg , TID ) Clavulanic acid  (187. 5 mg , TID ) And normal renal function ( CrCL :> 80 mL / Min), the free drug concentration With MIC  C _T Percentage of cases exceeding.

Ceft = ceftibutene; Clav = clavulanic acid; CrCL = creatinine clearance; MIC = minimum inhibitory concentration C _T = critical concentration; TID = 3 times a day.

Table 14: Cettig Butene  ( 300 mg , TID ) Clavulanic acid  ( 125 mg , TID ) And normal renal function ( CrCL :> 80 mL / Min), the free drug concentration With MIC  C _T Percentage of cases exceeding.

Ceft = ceftibutene; Clav = clavulanic acid; CrCL = creatinine clearance; MIC = minimum inhibitory concentration C _T = critical concentration; TID = 3 times a day.

Table 15: Cettig Butene  ( 300 mg , TID ) Clavulanic acid  (187. 5 mg , TID ) And normal renal function ( CrCL :> 80 mL / Min), the free drug concentration With MIC  C _T Percentage of cases exceeding.

Ceft = ceftibutene; Clav = clavulanic acid; CrCL = creatinine clearance; MIC = minimum inhibitory concentration C _T = critical concentration; TID = 3 times a day.

Example  8: Cephalosporin and CTX Interaction of -M-15

To assess why ceftivuten has a better clavulanate-induced PBLIE than the other cephalosporins tested, a series of degradation assays were performed. Cefotubesin assumed that ceftibuten was not rapidly degraded by ESBLs such as CTX-M-15 as rapidly as other cephalosporins such as cell TAps, Cefpodinsim, or Cefixime.

Direct measurement of the kinetic of CTX-M-15 mediated degradation (hydrolysis) of the four cephalosporins of ceftibuten, cytotoxic, cefpodocin, or cephem by direct measurement of the opening of the cephalosporin ring a turnover analysis was performed. About 100 mM Tris, pH 7, 0.02% Triton X-100, various concentrations of cephalosporin. The reaction was initiated by adding CTX-M15 to a 96 well, UV compatible plate. Hydrolysis was determined by measuring the absorbance at 260 nm over time using an Envision plate reader. GraphPad was used to fit the linear progression of cephalosporin turnover. The linear fit was used to find the slope (speed) of the cephalosporin turnover. The observed rate was plotted against the cephalosporin concentration to determine the kinetic parameters of interest.

The decomposition was assumed to follow the model:

E is CTX-M-15 and C is cephalosporin.

.

.

The IC ₅₀ of each cephalosporin was also measured using competitive assay with nitrocefin. About 0.01 nM CTX-M-15, 10 μM nitrocefin, and 2-fold dilution of a series of cephalosporins ranging from 0 to 500 μM added to 96-well plates. The knot loserpin turnover was determined by measuring the absorbance over time at 486 nm using a VersaMax plate reader. GraphPad was used to tailor the linear progression of the knot rosopin turnover to a function of cephalosporin concentration. The data were fitted to a three-parameter decomposition curve to generate IC ₅₀ values for each cephalosporin. The results of the two analyzes are shown in Table 16.

Table 16: Cephalosporin  Measured CTX -M-15 kinetics  parameter

Cefotutéen did not saturate the CTX-M-15 activity and did not compete with nitroxepine up to 1 mM. In contrast, and the saturation sepik planted CTX-M-15 activity at 14 μM and compete with IC ₅₀ = knitted rosepin at 20μM.

The measured kinetic constants were used to generate a simulated graph of percentage of remaining cephalosporin over time (Figure 8). Under non-saturating conditions, ceftivuten was degraded by CTX-M-15 to about 2.5, 67, and 70 times slower than cefixime, Cefpodocin, and Cephotacum, respectively.

The PBLIE experiments described in Example 6 were performed with a cephalosporin concentration in the MIC, for example, 2 μg / mL (~5 μM) for ceftibuten, and the concentration of ceftibuten in this example was non-saturation .

Example  9: In vivo drug-drug interactions

Although both ceftibuten and clavulanate are known to be well tolerated, it is not known whether the combination of the two drugs causes drug-drug interactions (DDI). To determine the potential of DDI, 34.5 mg / kg ceftibuten, 10.8 mg / kg clavulanic acid (clavulanate), or 34.5 mg / kg Sprague-Dawley rats (n = 6 per cohort) A large oral bolus of cefytutaine and 10.8 mg / kg clavulanic acid (clavulanate) was administered. This dose is based on a 70 kg human body weight and industrial FDA guidelines: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (FDA 2005) Was evaluated to be equivalent to the dose of the combination.

Plasma concentrations of ceftibuten or clavulanate at various time points were measured using standard methods and the results are shown in Figures 9A-9B, respectively. As shown in FIG. 9A, administration of ceftutin and clavulanic acid combination did not significantly change plasma concentrations of ceftibuten compared to cefotibuten alone. As shown in FIG. 9B, administration of ceftutin and clavulanic acid combination did not significantly change plasma concentrations of clavulanic acid compared to clavulanic acid alone.

Pharmacokinetic parameters were calculated and are shown in Table 17 below. A comparison of parameters for the test article between single and combination doses using a two-tailed t-test revealed statistically significant differences for some parameters. These data are consistent with the limited potential for drug-drug interactions between the two components, given that the maximum concentration did not change in one of the analytes and ceftivuten exposure was reduced to less than 17%.

Table 17

^The values after concomitant administration differ from the individual doses (P < 0.05)

Example  10: Compound urinary tract infection in mice cUTI ) In the model Cettig Butene  And Clavulanate  efficacy

The efficacy of ceftibuten plus clavulanate was evaluated in a mouse combined urinary tract infection (cUTI) model for clinical isolates of E. coli expressing ESBL CTX-M-15. Mice were infected with an injection of transurethral urethral inoculum. Treatment was initiated using q4h (every 4 hours) regimen on day 4 post-infection and the mice were subcutaneously administered with ceftibutene alone, ceftibuten plus clavulanate or the mellifenem control. Ceptibuten dose ranged from 0.25 to 4 mg / kg, and a fixed dose of clavulanate of 5 mg / kg was used to assess cefotibuten + clavulanate combinations. The mice were euthanized at 4 and 7 days post-infection. Urine, kidneys, and bladder were collected to evaluate the bacterial load measured in CFU numbers. The results are shown in Figures 10A-10C.

Administration of ceftibutene alone at 0.25-4 mg / kg (q4hr) for 3 days resulted in an administration response in this model. Compared to the untreated control group, 0.5-4 mg / kg dose of the three Petit butene kidney (4.26-5.83 log ₁₀ CFU) in the 0.6-2.17 log ₁₀ CFU (FIG. 10A), the bladder (4.06-4.58 log ₁₀ to CFU) to 2.8-3.35 log ₁₀ CFU (Figure 10B), urine (3.62-4.81 log ₁₀ CFU) to 2.46-3.65 log ₁₀ CFU (Figure 10C). As shown in FIGS. 10A-10C, the addition of clavulanate to doses of these ceftibutens resulted in further reductions in renal, bladder, and urinary CFU, respectively. In the kidney, the bacterial titer was 0.45-1.46 log ₁₀ CFU lower in the 0.25 / 5 and 4/5 mg / kg dose combination compared to the same dose of cefotibutene alone (FIG. 10A). 0.25 / 5 and 4/5 mg / kg for the bacteria in the combination dosage tie emitter bladder (Figure 10B) 0.86-1.89 log ₁₀ CFU and urine (Fig. 10C) from 1.57-1.85 log ₁₀ CFU was lower in the. Meropenem (4 mg / kg, q4hr) reduced bacterial CFU to 3.11, 3.75 and 3.25 log ₁₀ CFU in the kidney, bladder and urine, respectively.

The addition of clavulanate reduced bacterial titer in the kidney, bladder and urine as compared to cefotubutin alone. This data indicates that the combination of ceftibuten with the? -Lactamase inhibitor clavulanate improves the in vivo efficacy against ESBL-producing enterobacteriacease.

Example  11 In healthy adults Cettig Butene  And Clavulanate  Combination safety, tolerance and pharmacokinetics (PK)

(SD) and multiple doses (MD) of ceftibuten and clavulanate or placebo in healthy subjects to assess the safety, tolerability and pharmacokinetics (PK) of ceftibuten and clavulanate in healthy subjects ) Studies were conducted with orally administered in separate capsules, alone or in combination.

At an initial cohort of subjects receiving 400 mg ceftibuten / 125 mg clavulanate twice a day, 6 subjects received randomized active drug and 2 received randomized placebo. Following randomization of the subjects, subjects were treated with either 400 mg ceftibutene or SD of placebo (3 days), 48 hours after single dose (SD) of 125 mg clavulanate or placebo (1 day) After washing, they received a combination of ceftivuten 400 mg + clavulanate 125 mg or placebo (5 days). The subjects were then given a combination of ceftivuten 400 mg plus clavulanate 125 mg or placebo twice a day for 14 days (6 days - 19 days). For each dose, the subject received two ceftibuten 200 mg capsules and clavulanate 125 mg capsules. The divided doses of the study drug were administered at approximately 12 hour intervals. All subjects randomized to placebo received a placebo oral capsule equivalent to the study drug capsule and were given the same amount of capsule as the same dosing schedule as the randomly extracted subject in combination with ceftibuten and clavulanate.

The first daily dose of all SDs and the MD period on day 19 was given during the fasting period of the subject. Fasting was defined as fasting at least 10 hours before dosing and at least 4 hours overnight after SD administration. All other doses during the MD period were administered on a fasting day (at least 1 hour prior to meals or 2 hours after meals), except for 6 days of MD period, and the first dose on that day was high-fat, 30 minutes.

The safety and tolerability of ceftibuten and clavulanate were monitored throughout the course of clinical studies of adverse effects (AEs) and measurements of repeated clinical evaluations included: biomedical signals (temperature, blood pressure (BP), heart rate , And respiratory rate), physical examination, electrocardiogram, differential blood count (CBC) with differential, serum chemistry, liver function tests, and urinalysis.

For PK evaluation, blood and urine samples were collected from the subject for some aspects of analysis, corresponding to ceftibuten, clavulanate, and metabolites. Blood samples for plasma PK were collected at various time points prior to dosing and at 1, 3 and 5 days on SD and at the first dose on days 6 and 9 of study. In addition, blood samples were collected for evaluation of trough (pre-dose) concentrations on days 7, 8, and 9 and on alternate days after 17 days of study. At various intervals (~ 4-12 h intervals), urine was collected and integrated after SDs on days 1, 3, and 5 and after the first administration on day 19.

Preliminary PK data of amiketone metabolites of ceftibuten, clavulanate and clavulanate were evaluated after administration on Day 1, Day 3, and Day 5 of the study. PK parameters were estimated from the individual plasma concentration-time profiles using noncompartmental analysis (NCA) within Phoenix (Pharsight, Mountain View, Calif.), And Table 18 and Table 19 show cefictutene and clavulanate Respectively. Peak concentrations (C _max), C _max is the time (T _max) observed concentration - the area (AUC _inf) of infinity to the following time curve, coefficient of variation percent (% CV), elimination half-life (T _1/2), The apparent total elimination (CL / F) of the drug from plasma after oral administration and the apparent volume distribution (Vz / F) during the final step after non-intravenous administration were measured. No major drug-drug interactions (DDI) were observed after co-administration of a single oral dose of ceftibuten (2 x 200 mg) and clavulanate (1 x 125 mg) capsules.

PK parameters for ceftibutene were generally similar when ceftibuten was administered alone and in combination with clavulanate. The geometric mean C _max was slightly decreased, while the geometric mean T _max (time at which C _max was observed) was slightly delayed, but AUC _inf slightly increased slightly with either alone or in combination with clavulanate (Table 18). (C _max and AUC _inf ), as assessed by geometric mean% CV values ranging from 11 to 16% for cefotubentin alone and 15 to 31% for _{cefotybutene combination} , , Respectively.

PK parameters for clavulanate were similar when administered alone and in combination with ceftibuten (Table 19). Exposure to clavulanate was very variable, with either alone or in combination with ceftibuten, with geometric mean% CV for C _max and AUC _inf of approximately 80%. The amino ketone metabolism of clavulanate Sieves account for approximately 8.5% and 6.5% of parental exposure, respectively, when clavulanate is administered alone and in combination with ceftibuten.

Overall, these preliminary data demonstrate that there is no clear drug-drug interaction (DDI) between ceftibuten and clavulanate following a single oral dose. Changes in clavulanate PK parameters may be caused by a subject with abnormally low exposure.

Table 18. After single administration Ceptibuten  Summary of PK parameters for

Table 19. Post-dose On clavulanate  Summary of PK parameters for

An additional healthy group of subjects was a single dose (SD) and multiple dose (MD) similar to those described above, except for alternative dosing regimens that included administration of ceftibuten 400 mg / clavulanate 125 mg three times daily (TID) As a therapy, ceftibuten and clavulanate or placebo were orally administered alone or in combination as separate capsules. Similar to the above, 6 subjects received randomized active drug and 2 received randomized placebo. In this additional group, subjects were treated with either 400 mg ceftibuten or SD of placebo (3 days), 48 hours wash (1 day) after a single dose (SD) of 125 mg clavulanate or placebo Later, the combination of ceftivuten 400 mg + clavulanate 125 mg or placebo (5 days), and then combination of ceftivuten 400 mg + clavulanate 125 mg or placebo three times a day (TID), 14 Days (6 days - 19 days). Safety, tolerance and PK were evaluated as described above.

One or more additional cohort (s) of a healthy subject may be safely administered as described above after administration of alternate dosing regimens of ceftibuten and clavulanate until the maximum total daily dose of ceftivuten 1.8 g and 750 mg clavulanate , Tolerance and PK. In each additional cohort, similar to the SD and MD study period, 6 subjects received randomized active drug and 2 received randomized placebo. Exemplary dosing regimens are presented as follows:

· 300 mg ceftibutene / 187.5 mg clavulanate 3 times a day: the subject was treated with 300 mg ceftibuten or placebo after a 48-hour wash (day 1) after single dose (SD) of clavulanate or placebo 187.5 mg , Followed by a combination of ceftibuten 300 mg plus clavulanate 187.5 mg or placebo (5 days) followed by a combination of ceftibuten 300 mg plus clavulanate 187.5 mg or I received placebo three times a day (TID) and 14 days (6 days - 19 days).

· 400 mg ceftibutene / 187.5 mg clavulanate 3 times a day: the subject was treated with 400 mg ceftibuten or placebo after 48 hours of washing (day 1) after single dose (SD) of clavulanate or placebo 187.5 mg , Followed by a combination of ceftibuten 400 mg + clavulanate 187.5 mg or placebo (5 days) followed by a combination of ceftibuten 400 mg + clavulanate 187.5 mg or I received placebo three times a day (TID) and 14 days (6 days - 19 days).

Example  12 with kidney dysfunction In patients Cettig Butene  And Clavulanate  Combination safety, tolerance and Pharmacokinetics  (PK)

To assess safety, tolerance and pharmacokinetics (PK) in patients with renal dysfunction, subjects with normal or severe renal dysfunction were administered with a single dose (SD) of ceftibuten and clavulanate in combination . Subjects with normal renal dysfunction have a creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation and the most recent serum creatinine collected within a screening interval of ≥ 30 mL / min to <60 mL / min. Subjects with normal renal dysfunction have a creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation and the most recent serum creatinine collected within a screening interval of ≥ 15 mL / min to <30 mL / min. For both groups, the subjects were administered 400 mg ceftibuten and 125 mg clavulanate in separate capsules.

Stability and pharmacokinetic analyzes were performed. The safety and tolerability of ceftibuten and clavulanate were monitored by clinical evaluations of AEs and measurements of repeated clinical evaluations including: vital signs (temperature, blood pressure (BP), heart rate, and respiration rate), body Laboratory tests such as test, electrocardiogram, differential blood count (CBC) with differential, serum chemistry, liver function test and urine test. Differential Whole blood counts and blood samples for blood chemistry and serum chemistry and urine samples for urine were collected on the 8th post-SD days after SD. CBCs include hemoglobin, hematocrit, platelet count, red blood cell count, white blood cell count, and percentage or absolute differentiation (neutrophils, lymphocytes, and other cells). Serum chemistry includes sodium, potassium, chloride, magnesium, bicarbonate, glucose, blood urea nitrogen (BUN), creatinine, uric acid, and albumin. Urinalysis includes color, transparency / turbidity, pH, specific gravity, glucose, ketone, nitrite, leukocyte esterase, protein, RBCs, WBCs, epithelial cells, casts, and crystals. Liver function is also performed once within two hours after SD-dose and once-daily after SD-dose and once every eight days. Liver function tests include aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, and direct bilirubin.

Blood and urine samples were collected for analysis of ceftivuten, clavulanate and, in some cases, concentrations corresponding to the metabolites. Platelets for PK analysis were collected for analysis at various time points throughout the 96-hour period prior to dosing-up to 10 minutes and SD-of single combination dosing. At various intervals (~ 4 to 12 hours apart), urine was collected and integrated after oral drug administration throughout SD-after 96 hours of single combination administration. In some cases, each subject with normal and severe renal dysfunction, compared to PK, was treated with age (+/- 10 years), age BMI (± 15%), race, and gender.

Example  13 Multiple urinary tract infections, including acute pyelonephritis (AP) cUTI ) In patients Cettibuten and Clavulanate  Combination therapy

The combination of ceftibuten and clavulanate is administered orally to adult patients with multiple urinary tract infections (cUTIs), including acute pyelonephritis (AP). In some embodiments of the invention, the cUTI or AP diagnostic criteria are generally consistent with FDA guidelines for cUTI. The patient has at least two signs and / or symptoms of infection and the cUTI patient has at least one complication factor (e.g. urinary incontinence, urethral catheter insertion, structural or anatomical abnormality of the urinary tract, or at least 100 mL of residual urine Men with experienced neurological deficits).

Ceftibuten and clavulanate were administered as oral capsules of BID or TID divided daily doses, as described in Example 11, for 7 to 10 days of treatment. Safety and efficacy were assessed during treatment and at the end of treatment (EOT) visit. Patients were also evaluated for safety and efficacy at a later time point after treatment, such as approximately 17 days and / or approximately 28 days.

The primary efficacy endpoint is the combined clinical and microbiological rate of treatment, such as 17 days, in patients with a microbiologically modified intent-to-treat (mMITT) population for treatment. Clinical and microbiological endpoints were evaluated in the Treatment Route (EOT) as a secondary endpoint.

Safety and efficacy are also compared to currently approved IV therapies given over 7 to 10 days of treatment. Examples of IV comparative compounds include IV carbapenem (e.g., ertapenem, meropenem or imipenem / cilastatin) and a beta-lactam / beta-lactamase inhibitor combination For example ceftolozane / tazobactam or piperacillin / tazobactam). The use of IV comparators has been shown to provide a clinically meaningful comparison to demonstrate the efficacy of ceftibuten plus clavulanate in patients with cUTI, including the consequences of ESBL-producing or fluoroquinolone-resistant enterobacteriaceae ESBL- The use of an IV comparator is essential, since oral antibiotics are not available for use in generating enterobacteriaceae.

The present invention is not intended to be limited in scope to the specific disclosed embodiments which are provided to illustrate various aspects of the invention, for example. Various modifications to the described compositions and methods will become apparent from the description and teachings herein. Such variations can be made without departing from the true scope and spirit of the disclosure of the present invention and are intended to be included within the scope of the present disclosure.

Claims (161)

A method of treating an Enterobacteriaceae bacterial infection of an individual,
(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And
(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,
Orally to the subject,
The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);
A method characterized by at least one of the following (i) to (iii):
(i) component (a) is administered to said individual at a total daily dose of 800-1800 mg;
(ii) component (b) is administered to said individual in a total daily dose of 250-750 mg;
(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day. A method for preventing an Enterobacteriaceae bacteria infection in an individual,
(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And
(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,
Orally to the subject,
The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);
A method characterized by at least one of the following (i) to (iii):
(i) component (a) is administered to said individual at a total daily dose of 800-1800 mg;
(ii) component (b) is administered to said individual in a total daily dose of 250-750 mg;
(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day. 3. The method according to claim 1 or 2, wherein components (a) and (b) are administered together in the same pharmaceutical composition. A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual,
(a) orally administering ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, to said individual,
The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);
Component (a) is administered in a total daily dosage of 800-1800 mg and / or in divided doses at least twice per day, wherein the divided dose of component (a) is about 300-400 mg;
Wherein component (a) is administered in combination with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is administered in a total daily dosage of about 250-750 mg and / Wherein the divided dose of component (b) is about 100-250 mg. A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual,
(b) orally administering clavulanic acid, or a pharmaceutically acceptable salt thereof, to said individual,
The bacterial infection is caused by enterobacteriaceae expressing extended-spectrum beta-lactamase (ESBL);
Component (b) is administered in a total daily dose of 250-750 mg and / or in divided doses more than once a day, wherein the divided dose of component (b) is about 100-250 mg;
Component (b) is administered together with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is administered in a total daily dose of about 800-1800 mg and / Wherein the divided dose of component (a) is about 300-400 mg. 6. The method of any one of claims 1 to 5 wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infections, neonatal sepsis, An intra-abdominal infection, an otitis media, or a wound infection,
Optionally, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infection (cIAI) or community acquired pneumonia (CAP). A method of treating an Enterobacteriaceae bacterial infection of an individual,
(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And
(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,
Orally to the subject,
The bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media,
Alternatively, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonia (CAP); And / or
Wherein said bacterial infection is caused or associated with enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL). A method for preventing an Enterobacteriaceae bacteria infection in an individual,
(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And
(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,
Orally to the subject,
The bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media,
Alternatively, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonia (CAP); And / or
Wherein said bacterial infection is caused or associated with enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL). CLAIMS What is claimed is: 1. A method of treating a bacterial infection of an individual,
(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And
(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,
Orally to the subject,
Wherein said bacterial infection is caused by enterobacteriaceae expressing an expanded-spectrum beta-lactamase (ESBL), said subject having previously been administered an antibiotic to treat said bacterial infection. 10. The process according to any one of claims 1 to 9, wherein the component (a) is cefthuthene dihydrate. 11. The method according to any one of claims 1 to 10, wherein component (b) is potassium clavulanate. 12. A method according to any one of claims 1 to 11, wherein component (a) is administered simultaneously, concurrently or sequentially with component (b). 13. The method according to any one of claims 7 to 12, wherein components (a) and (b) are co-administered with the same pharmaceutical composition. 14. The method according to any one of claims 1 to 13, wherein component (a) is administered to said individual at a ratio of 1: 1 to 7: 1 to component (b). 15. The method according to any one of claims 1 to 14, wherein component (a) is administered to said subject in a ratio of 1: 1 to 3: 1 to component (b). 16. The method according to any one of claims 7 to 15, wherein the method is characterized by at least one of the following (i) to (iii):
(i) component (a) is administered to said individual at a total daily dose of 800 to 1800 mg;
(ii) component (b) is administered to said individual at a total daily dose of 250-750 mg;
(iii) the total daily dose of one or both of components (a) and (b) is administered in divided doses more than once per day. The method according to any one of claims 1 to 3, 6, and 10 to 16, characterized in that the total daily dose is divided into more than 2 divided doses per day RTI ID = 0.0 &gt; administered &lt; / RTI &gt; The method according to any one of claims 1 to 3, 6 and 10 to 17, characterized in that the total daily dose is divided into two or more divided doses per day RTI ID = 0.0 &gt; administered &lt; / RTI &gt; The method according to any one of claims 1 to 3, 6, and 10 to 18, wherein the method is characterized by (i), (ii) and (iii). 20. The method according to any one of claims 1 to 6 and 10 to 19, wherein the total daily dose of one or both of the components (a) and (b) is 2-5 times divided per day RTI ID = 0.0 &gt; administered &lt; / RTI &gt; 20. A method according to any one of claims 1 to 6 and 10 to 20, wherein the total daily dose of one or both of the components (a) and (b) is administered twice or three times per day Wherein the dose is administered in divided doses. 22. A method according to any one of claims 1 to 6 and 10 to 21, wherein the divided doses of component (a) are administered in an amount of about 300-600 mg of component (a) / RTI &gt; 22. The method according to any one of claims 1 to 6 and 10 to 22, wherein the divided dose of the component (a) is about 300-400 mg of component (a). 24. The method according to any one of claims 1 to 23, wherein component (a) is administered in a total daily dosage of 900-1200 mg. A pharmaceutical composition according to any one of claims 1 to 6 and 10 to 24, wherein the divided dose of component (b) is administered in an amount of about 100 to 250 mg of component (b) / RTI &gt; 26. The method according to any one of claims 1 to 25, wherein component (b) is administered in a total daily dose of 375-562.5 mg. A method of treating or preventing an Enterobacteriaceae bacterial infection of an individual,
(a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; And
(b) clavulanic acid, or a pharmaceutically acceptable salt thereof,
Orally to the subject,
The bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media,
Alternatively, the bacterial infection is a combined urinary tract infection (cUTI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonia (CAP); And / or said enterobacteriaceae expressing magnified-spectrum beta-lactamase (ESBL);
(i) the components (a) and (b) are administered in divided doses two or three times a day, wherein the divided dose of component (a) is about 300-400 mg, ) Is about 100-250 mg; And / or
(ii) component (a) is administered at a total daily dose of 900-1200 mg and component (b) is administered at a total daily dose of 375-562.5 mg. 28. The method according to any one of claims 1 to 6 and 10 to 27, wherein the divided dose of the component (b) is about 125-187.5 mg. 28. The method according to any one of claims 1 to 6 and 10 to 28, wherein the divided dose of component (a) is about 400 mg. 29. The method according to any one of claims 1 to 6 and 10 to 29, wherein the divided dose of component (a) is about 300 mg. 31. The method according to any one of claims 1 to 6 and 10 to 30, wherein the divided doses of component (b) are administered in an amount of about 300 mg. 31. A method according to any one of claims 1 to 6 and 10 to 31, wherein the divided doses of component (b) are administered in an amount of about 187.5 mg. 33. A composition according to any one of claims 1 to 32, wherein one or both of components (a) and (b) are in capsules, solutabs, sachets, suspensions, or tablets. &Lt; / RTI &gt; 34. The method of any one of claims 1 to 33, wherein one or both of components (a) and (b) are formulated into a capsule, wherein the capsule is 0, 1 or 2 in size. 34. The method of any one of claims 1 to 34, wherein one or both of components (a) and (b) are formulated for modified or extended release. 34. The method according to any one of claims 1 to 35, wherein the Enterobacteriaceae bacteria are selected from the group consisting of Citrobacter freundii ), Enterobacter aerogenes , Enterobacter cloacae), E. coli (Escherichia coli), keulrep when Ella pneumoniae (Klebsiella pneumoniae , or Klebsiella oxytoca . 37. The method of any one of claims 1 to 36 wherein the bacterial infection is complex UTI or acute pyelonephritis. 37. The method of any one of claims 1 to 37, wherein the method is characterized by one or more of the following:
(i) said ESBL is inhibited by component (b);
(ii) the IC ₅₀ of component (a) is greater than about 100 μM or 1000 μM for the ESBL;
(iii) the K _M of the component (a) is greater than about 100 μM for the ESBL;
(iv) administration of the component (a) and component (b) is carried out in an amount greater than 40% fT> MIC, greater than 50% fT> MIC, or greater than 60% Causes systemic exposure;
(v) administration of the components (a) and (b) comprises administering an effective amount of a compound of formula (b) greater than 20% fT> CT, greater than 25% fT> CT, greater than 30% RTI ID = 0.0 > of: &lt; / RTI >
(vi) the PBLIE of component (b) in combination with component (a) is at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours;
(vii) when used in combination with component (b), the MIC of component (a) is less than or equal to about 4 ug / mL, less than about 2 ug / mL, less than about 1 ug / mL, ego;
(viii) the MIC of the component (a) alone is about 4-fold higher than the MIC of the component (a) when used in combination with the component (b) against the same enterobacteriaceae, alternatively ESBL-producing enterobacteriaceae Or more;
(ix) when used in combination with component (b), the MBC of component (a) is used in combination with component (b) for the same enterobacteriaceae, optionally ESBL-producing enterobacteriaceae, Is 4 or 2 times higher than the MIC of component (a) when used;
(x) administration of the component (a) and component (b) comprises administering about 10 ug / mL to about 30 ug / mL, 10 ug / mL to 25 ug / mL, 15 ug / mL to about 30 Mu] g / mL, or 15 [mu] g / mL to about 25 [mu] g / mL, optionally the maximum concentration is the maximum serum concentration; And / or
(xi) the maximum concentration of said component (b) is from about 0.2 ug / mL to about 5 ug / mL, from 0.2 ug / mL to 4 ug / mL, from 0.2 ug / mL to about 3 ug / mL, About 4 / / mL, 1 / / mL to about 4 / / mL, 1 / / mL to about 3 / / mL, and optionally the maximum concentration is the maximum serum concentration. 39. The method of any one of claims 1 to 38, wherein the ESBL is CTX-M, TEM, or SHV beta-lactamase. 40. The method according to any one of claims 1 to 39, wherein the ESBL is CTX-M-14 or CTX-M-15 or CTX-M group identical to CTX-M-14 or CTX-M-15. 40. The method according to any one of claims 1 to 40, wherein said bacteria express CTX-M-14. 42. The method according to any one of claims 1 to 41, wherein said bacteria express CTX-M-15. 43. The method of any one of claims 1 to 42, wherein the bacteria further expresses one or more additional beta-lactamases. 44. The method of claim 43, wherein said at least one additional beta-lactamase is independently CTX-M, FEC, KLUA, KLUG, TEM, TOHO, or SHV beta-lactamase. 44. The method of claim 43 or 44 wherein said at least one additional beta-lactamase is selected from the group consisting of CTX-M, CTX-M-1, CTX-M-2, CTX- CTX-M-9, CTX-M-9, CTX-M-9, CTX-M- M-12, CTX-M-13, CTX-M-14, CTX-M-15, CTX-M-16, CTX- 21, CTX-M-22, CTX-M-23, CTX-M-24, CTX-M-25, CTX-M- 1, KLUA-5, KLUA-6, KLUA-8, KLUA-9, KLUA-10, KLUA-11, KLUG-1, SHV-2, SHV- Or TOHO-1. 45. The method of any one of claims 43-45 wherein said at least one additional beta-lactamase is selected from the group consisting of CTX-M-1, CTX-M-3, CTX-M-14, SHV-2, SHV-7, SHV-12, TEM-1, or TEM-OSBL. 46. The method of any one of claims 1 to 46, wherein said bacteria have an antibiotic resistance phenotype. 48. The method of claim 47, wherein the antibiotic resistance phenotype is resistance to a combination of fluoroquinolone, beta-lactam, or beta-lactam: beta-lactamase inhibitor. 48. The method of claim 47 or 48 wherein said antibiotic resistant phenotype is selected from the group consisting of amikacin, amoxicillin, ampicillin, aztreonam, cefaclor, cefadroxil ), Cefepime, cefixime, ceftibuten, cefdinir, cefditoren, cefotaxime, cefpodoxime, The use of cefprozil, ceftaroline, ceftazidime, ceftriaxone, cefuroxime, cephalexin, cephradine, ciprofloxacin, the compounds of the present invention can be used in combination with ciprofloxacin, doripenem, gentamicin, imipenem, levofloxacin, loracarbef, meropenem, piperacillin, / RTI &gt; is resistant to tobramycin. 49. The method of any one of claims 47 to 49 wherein the antibiotic resistance phenotype is ST131. 50. The method according to any one of claims 1 to 50, wherein the bacteria do not express a protein selected from the group consisting of AmpC, KPC, OXA, NDM, or OMP. 52. The method of any one of claims 1 to 51, wherein said bacteria do not express AmpC. 52. The method according to any one of claims 1 to 52, wherein said bacteria do not express KPC. 50. The method of any one of claims 1 to 50, wherein said bacteria do not express OXA. 54. The method of any one of claims 1 to 54, wherein said bacteria do not express NDM. 55. The method according to any one of claims 1 to 55, wherein the bacteria does not express OMP. 56. The method of any one of claims 1 to 8 and 56 to 56 wherein the subject has previously been administered an antibiotic to treat the bacterial infection. 57. The method of claim 9 or 57, wherein the previously administered antibiotic is beta-lactam or fluoroquinolone. 58. The method of any one of claims 9-57, wherein said previously administered antibiotic is not sufficiently effective in treating a bacterial infection. The method of any one of claims 9 and 57 to 59, wherein said previously administered antibiotic is an intravenously administered antibiotic. 60. The method according to any one of claims 1 to 60, wherein the administration of components (a) and (b) is a step-down therapy or an intravenous, oral therapy switch. Lt; / RTI &gt; 62. The method according to any one of claims 1 to 61, wherein components (a) and (b) are administered together with the food. 62. The method of any one of claims 1 to 61, wherein components (a) and (b) are administered without food. 63. The method of any one of claims 1 to 63, wherein the subject has renal dysfunction. 64. The method of any one of claims 1-64, wherein components (a) and (b) are administered on an outpatient basis and / or self-administered by said individual. 66. The composition of any one of claims 1 to 65 wherein components (a) and (b) are at least about or about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 14, 15, 16, 17, 18, 19, or 20 days after administration to the subject. 66. The method of any one of claims 1-66, wherein components (a) and (b) are administered for about 7 to 10 days. 67. The method of any one of claims 1-67, wherein the subject is a human. A method for the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection comprising the steps of: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, As a salt,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
The medicament is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) and component (b) Wherein said divided dose is characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. 70. The use according to claim 69, wherein component (a) and component (b) are combined in a single dosage form. 70. The use according to claim 69, wherein component (a) and component (b) are provided in separate dosage forms. A method for the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection comprising the steps of: (a) using ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
The medicament is used for the oral administration of the divided doses of component (a) to the individual;
Component (a) is administered with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is orally administered in divided doses;
Wherein the components (a) and (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. (B) the use of clavulanic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing an enterobacteriaceae bacterial infection,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
Said medicament is used for the oral administration of a divided dose of component (b) to a subject;
Component (b) is administered with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is orally administered in divided doses;
Wherein the components (a) and (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. A method for the manufacture of a medicament for treating or preventing an Enterobacteriaceae bacterial infection comprising the steps of: (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, As a salt,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Wherein the components (a) and (b) are formulated for oral administration. 74. The method of claim 74, wherein said medicament is used to orally administer a divided dose of component (a) and a divided dose of component (b) to said individual, wherein said component (a) Wherein said divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. 78. The use of claim 75, wherein component (a) and component (b) are combined in a single dosage form. 78. The use of claim 75, wherein component (a) and component (b) are provided in separate dosage forms. (A) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an Enterobacteriaceae bacterial infection, A pharmaceutical composition comprising:
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
The pharmaceutical composition is used for the oral administration of divided doses of component (a) and divided doses of component (b) to a subject, wherein component (a) and component (b) Wherein the divided dose is characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. 79. The pharmaceutical composition of claim 78, wherein component (a) and component (b) are combined in a single dosage form. 80. The pharmaceutical composition of claim 79, wherein component (a) and component (b) are provided in separate dosage forms. A pharmaceutical composition comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the treatment or prevention of an Enterobacteriaceae bacteria infection,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
The pharmaceutical composition is used for the oral administration of divided doses of component (a) to a subject;
Component (a) is administered with (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, and component (b) is orally administered in divided doses;
Wherein the component (a) and the component (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. A pharmaceutical composition comprising (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for treating or preventing an Enterobacteriaceae bacterial infection,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
The pharmaceutical composition is used for the oral administration of divided doses of component (b) to a subject;
Component (b) is administered with (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein component (a) is orally administered in divided doses;
Wherein the component (a) and the component (b) are administered in divided doses at least twice per day and the divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. A pharmaceutical composition comprising (a) ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, for treating or preventing an Enterobacteriaceae bacterial infection As a pharmaceutical composition,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Wherein said pharmaceutical composition is formulated for oral administration. &Lt; RTI ID = 0.0 &gt; 21. &lt; / RTI &gt; 83. The composition of claim 83, wherein the composition is used to orally administer a divided dose of component (a) and / or a divided dose of component (b) to the individual, wherein component (a) Wherein the pharmaceutical composition is administered at a dosage of at least two divided doses per day and the divided dose is characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. 84. The pharmaceutical composition according to claim 83 or 84, wherein component (a) and component (b) are combined in a single dosage form. 84. The pharmaceutical composition according to claim 84 or 85, wherein component (a) and component (b) are provided in separate dosage forms. 87. The use or pharmaceutical composition according to any one of claims 69 to 86, wherein the component (a) is ceftuthene dihydrate. 87. The use or pharmaceutical composition according to any one of claims 69 to 87, wherein component (b) is potassium clavulanate. Wherein the component (a) and the component (b) are in the form of a mixture of the components (a), (b) and b) is for simultaneous, concurrent or sequential administration. The method according to any one of claims 69, 70, 72 to 76, 78, 79, 81 to 85, and 87 to 89, wherein component ) And component (b) are for administration together. (A) and the component (A), the component (A), the component (A) and the component (B) b) is for separate administration. 91. A pharmaceutical composition or use according to any one of claims 69 to 91, wherein component (a) and component (b) are administered on an outpatient basis and / or self-administered by said individual. 92. The use or pharmaceutical composition according to any one of claims 69 to 92, wherein component (a) is administered to said individual in a ratio of 1: 1 to 7: 1 to component (b). 93. The use or pharmaceutical composition according to any one of claims 69 to 93, wherein component (a) is administered to said individual in a ratio of 1: 1 to 3: 1 to component (b). 94. The use or pharmaceutical composition according to any one of claims 69 to 94, wherein said divided doses are administered 2-5 times per day. 95. The use or pharmaceutical composition according to any one of claims 69 to 95, wherein said divided doses are administered two to three times per day. 96. The use or pharmaceutical composition according to any one of claims 69 to 96, wherein the divided dose of the component (a) is 300-600 mg. 97. The use or pharmaceutical composition according to any one of claims 69 to 97, wherein the divided dose of the component (a) is 300-400 mg. 98. The use or pharmaceutical composition according to any one of claims 69 to 98, wherein the divided dose of component (a) is about 400 mg. The use or pharmaceutical composition according to any one of claims 69 to 99, wherein the divided dose of component (a) is about 300 mg of component (a). 112. The use or pharmaceutical composition according to any one of claims 69 to 100, wherein the total daily dose of said component (a) is from about 900 to 1200 mg. 102. The use or pharmaceutical composition according to any one of claims 69 to 101, wherein the divided dose of the component (b) is about 100-250 mg. 102. The use or pharmaceutical composition according to any one of claims 69 to 102, wherein the divided dose of the component (b) is about 125-187.5 mg. 111. The use or pharmaceutical composition according to any one of claims 69 to 103, wherein the total daily dose of said component (b) is from about 375 to 562.5 mg. 104. The use or pharmaceutical composition according to any one of claims 69 to 104, wherein the divided dose of component (b) is about 125 mg of component (b). 105. The use or pharmaceutical composition according to any one of claims 69 to 105, wherein the divided dose of component (b) is about 187.5 mg of component (b). 106. Use according to any one of claims 69 to 106, wherein one or both of the components (a) and (b) are formulated into a capsule, a solution tower, a suspension, a suspension or a tablet, . 107. A pharmaceutical composition according to any one of claims 69 to 107, wherein one or both of the components (a) and (b) are formulated into capsules and the capsules are 0, 1, . 108. The use or pharmaceutical composition according to any one of claims 69 to 108, wherein one or both of the components (a) and (b) are formulated for modified or extended release. 109. The method according to any one of claims 69 to 109, wherein the enterobacteriaceae bacteria are selected from the group consisting of Citrobacter freundii ), Enterobacter aerogenes , Enterobacter cloacae), E. coli (Escherichia coli), keulrep when Ella pneumoniae (Klebsiella pneumoniae , or Klebsiella oxytoca . 110. The use or pharmaceutical composition according to any one of claims 1 to 110, wherein the bacterial infection is complex UTI or acute pyelonephritis. 111. The use or pharmaceutical composition according to any one of claims 69 to 111, wherein said ESBL is CTX-M, TEM, or SHV beta-lactamase. 112. Use according to any one of claims 69 to 112, wherein the ESBL is CTX-M-14 or CTX-M-15 or a CTX-M group identical to CTX-M-14 or CTX- A pharmaceutical composition. 114. A pharmaceutical composition or use according to any one of claims 69 to 113, wherein component (a) and component (b) are for use in an individual to which an antibiotic has previously been administered to treat said bacterial infection. 114. The pharmaceutical composition or use according to claim 114, wherein the previously administered antibiotic is beta-lactam or fluoroquinolone. 114. A pharmaceutical composition or use according to any one of claims 69 to 115, wherein components (a) and (b) are administered with the food. 114. A pharmaceutical composition or use according to any one of claims 69 to 116, wherein components (a) and (b) are administered without food. 117. A pharmaceutical composition or use according to any one of claims 69 to 117, wherein said medicament or composition is for use in a subject having a renal insufficiency. The composition of any one of claims 69 to 118, wherein components (a) and (b) are at least about or about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 14 or 15 days, 16 days, 17 days, 18 days, 19 days, or 20 days after administration of the pharmaceutical composition. 119. The pharmaceutical composition or use according to any one of claims 69 to 119, wherein components (a) and (b) are administered for about 7 to 10 days. 120. The pharmaceutical composition or use according to any one of claims 69 to 120, wherein the subject is human. at least two oral dosage forms comprising (a) at least two oral dosage forms comprising ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and / or (b) clavulanic acid, or a pharmaceutically acceptable salt thereof, A kit comprising a plurality of oral dosage forms,
Each dosage form is intended for oral administration of a unit dose to a subject;
At least two oral dosage forms of the component (a) and / or at least two oral dosage forms of the component (b) may contain a divided dose of the component (a) and / or the component (b) more than once a day Wherein component (a) is administered in combination with component (b);
Wherein said divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. 124. The kit of claim 122, wherein component (a) and component (b) are combined in a single dosage form. 124. The kit of claim 122, wherein component (a) and component (b) are provided in separate dosage forms. 124. The kit of any one of claims 122 to 124, further comprising instructions for use of component (a) and component (b). 126. The kit of claim 125, wherein the instructions specify that the kit is for use in the treatment or prevention of an Enterobacteriaceae bacterial infection. 126. The method of claim 126, wherein the bacterial infection is selected from the group consisting of urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, (CUI), acute pyelonephritis, urolithiasis (uUTI), multiple intraabdominal infection (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is enlarged-spectrum beta-lactamase Lt; RTI ID = 0.0 &gt; (ESBL). &Lt; / RTI &gt; A kit for the treatment or prevention of an Enterobacteriaceae bacteria infection, comprising: (a) at least two oral dosage forms comprising ceftibuten or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and / or (b) clavulanic acid , &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof,
Said bacterial infection is a urinary tract infection (UTI), upper respiratory tract infection, lower respiratory tract infection, primary or catheter related blood infection, neonatal sepsis, intraperitoneal infection, otitis media, or wound infection, ), Acute pyelonephritis, simple urinary tract infection (uUTI), multiple intraperitoneal infections (cIAI) or community acquired pneumonitis (CAP) and / or the bacterial infection is caused by the expression of extended-spectrum beta-lactamase Caused by enterobacteriaceae;
Each dosage form is intended for oral administration of a unit dose to a subject:
At least two oral dosage forms of the component (a) and / or at least two oral dosage forms of the component (b) may contain a divided dose of the component (a) and / or the component (b) more than once a day Wherein component (a) is administered in combination with component (b);
Wherein said divided doses are characterized by one or more of the following:
(i) the divided dose of component (a) is for administration of a total daily dose of 800 to 1800 mg;
(ii) the divided dose of component (a) is at least about 300 mg;
(iii) the divided dose of component (b) is for administration of a total daily dose of 250-750 mg; And / or
(iv) the divided dose of component (b) is at least about or at least about 100 mg. 127. The kit of claim 128, wherein component (a) and component (b) are combined in a single dosage form. 129. The kit of claim 128, wherein component (a) and component (b) are provided in separate dosage forms. 130. The kit according to any one of claims 122 to 130, wherein said kit further comprises instructions for administration of component (a) and component (b) to said subject. 132. The kit of claim 131, wherein the instructions specify that the divided dosages of components (a) and (b) are for administration together. 132. The kit of claim 131, wherein the instructions specify that the divided doses of components (a) and (b) are for separate administration. A kit according to claim 131 or 134, wherein the instructions specify that the divided dose of the component (a) and the divided dose of the component (b) are for simultaneous, concurrent or sequential administration . A method according to any one of claims 131 to 134, wherein said instructions specify that said components (a) and (b) are administered on an outpatient basis and / or self-administered by said individual Kits. 135. The kit according to any one of claims 122 to 135, wherein said divided doses are administered 2-5 times per day. 136. The kit of any one of claims 122 to 136, wherein said divided doses are administered two to three times per day. 137. The use according to any one of claims 132 to 137, wherein the instructions further specify that the divided doses of component (a) and the divided doses of component (b) are administered 2-5 times per day . 137. The use according to any one of claims 132 to 137, wherein the divided doses of the component (a) and the divided doses of the component (b) are administered two to three times per day A kit that specifies. The kit according to any one of claims 122 to 139, wherein the divided dose of the component (a) is 300-600 mg. 143. The kit according to any one of claims 122 to 140, wherein the divided dose of the component (a) is 300-400 mg. 143. The kit according to any one of claims 122 to 141, wherein the divided dose of the component (a) is about 400 mg of component (a). 144. The kit according to any one of claims 122 to 142, wherein the divided dose of component (a) is about 300 mg of component (a). 143. The kit according to any one of claims 122 to 143, wherein the total daily dose of component (a) is from about 900 to 1200 mg. 144. The kit according to any one of claims 122 to 144, wherein the divided dose of component (b) is about 100-250 mg of component (b). 145. The kit according to any one of claims 122 to 145, wherein the divided dose of component (b) is about 125-187.5 mg of component (b). 146. The kit according to any one of claims 122 to 146, wherein the divided dose of the component (b) is from about 375 mg to about 532.5 mg. A kit according to any one of claims 122 to 147, wherein the divided dose of component (b) is about 125 mg of component (b). 143. The kit according to any one of claims 122 to 148, wherein the divided dose of component (b) is about 187.5 mg of component (b). 149. The kit of any one of claims 122 to 149, wherein said oral dosage form comprises a capsule, a solution tower, a suspension, a suspension, or a tablet. 152. The kit of any one of claims 122 to 150, wherein the oral dosage form is a capsule and the capsule is 0, 1, or 2 size. 152. The kit of any one of claims 122 to 151, wherein one or both of the oral dosage forms of component (a) and component (b) are formulated for modified or extended release. 152. The kit according to any one of claims 122 to 152, wherein component (a) is ceftuthene dihydrate. The kit according to any one of claims 122 to 153, wherein the component (b) is potassium clavulanate. A kit according to any one of claims 122 to 154, wherein component (a) and component (b) are packaged in the same container. 155. The kit according to any one of claims 122 to 155, wherein component (a) and component (b) are packaged in different containers. 156. The method of claim 155 or 156, wherein the container is a divided container and at least two oral dosage forms of the component (a) are separated from one another in the divided container and / Wherein the oral dosage form is separated from one another in the divided container. 156. The kit of claim 156 or claim 157 wherein the container is a blister pack. 67. The method of any one of claims 1-68, further comprising administering at least one additional antibiotic. 121. The pharmaceutical composition or use of any one of claims 69 to 121 for use with at least one additional antibiotic. 143. The kit of any one of claims 122 to 158, wherein the kit comprises at least one additional antibiotic.

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